# GenusMiliusa: A Review of Phytochemistry and Pharmacology

Authors: Ninh The Son
Journal: Evidence-Based Complementary and Alternative Medicine
 (2019)

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## Abstract

Background. GenusMiliusa (family Annonaceae), widely distributed in mainland Asia and Australia to New Guinea, has been employed in both traditional herbal uses and pharmacological medicines. Original research articles related to this genus are now available, but supportive reviews highlighting phytochemical and pharmacological aspects are now insufficient.Objective. This account is an overview of most of the compounds isolated from this genus, along with their pharmacological evaluations.Conclusion. A vast amount of data showed that genusMiliusa contained various classes of secondary metabolites. Herein, more than two hundred constituents were isolated, comprising alkaloids, geranylated homogentisic acids, flavonoids, lignans, neolignans, terpenoids, acetogenins, styryls, lactones, phenolics, amides, alcohols, and furfural derivatives. Novel miliusanes and bicyclic lactones have been remarkable characteristics ofMiliusa plants. Essential oils from these plants were also detected, with a high amount of β-caryophyllene. Numerousin vitro biological researches on, for example, anticancer, antifungal, antimycobacterial, anti-inflammation, and cardiac activity, especially in terms of cytotoxicity, using either isolated compounds or plant extracts, implied thatMiliusa phytochemical components now set out to have a key role in pharmacological development.M. smithiae ethyl acetate extract and its flavonoid ayanin (75) inhibited the growth of MCF-7 cell line comparable with positive control ellipticine. (+)-Miliusol (72) stimulatedin vivo anticancer experiment against HCT116 xenograft mouse tumor following the p21-dependent induction of cellular senescence mechanism.


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## Body

## 1. Introduction

People around the world have been extensively using herbal plants and their products for healthcare objectives. As can be seen, the aromatic medicinal plants have been extensively researched as an important resource of commercial drugs because of their wide traditional uses and pharmacological potencies [1]. Natural products are also recognized to be among the richest resources for new drugs and/or drug leaders due to their high structural diversity as they are not available throughout synthetic pathways [2]. GenusMiliusa (family: Annonaceae) comprises about 60 species and is widely native throughout India and Bhutan to Australia and New Guinea, but mostly found in many Asia countries such as Vietnam, Thailand, and China [3].More than thirty newly rare secondary metabolites belong to derivatives of geranylated homogentisic acid; in particular, the serial novel miliusanes I-XXXI could be seen as characteristic signals to recognize plants from genusMiliusa.Phytoconstituents derived fromMiliusa plants were subjected to cytotoxic activity, acetylcholinesterase inhibition, activation of cardiac myosin ATPase, anticancer, antifungal, antibacterial, antimalaria, anti-inflammation, anti-herpes, and antioxidant activity [4–14].In Southeast Asian traditional medicines,M. balansae species was used for gastropathy and glomerulonephropathy,M. velutina was recommended as tonic and aphrodisiac medicine, or with Thai people,M. thorelii species, also known as “Maa-Dam”, was applied to analgesic treatment [7, 8].Secondary metabolites from medicinal plants of genusMiliusa are renowned for traditional uses and pharmaceutical potentials. However, there have not been specific reviews to assess the value of this genus, to the best of our knowledge. The current paper deals with most researches over the past 20 years related toMiliusaspecies and has given a great insight into the botanical description, the correlated chemical isolated compounds in phytochemical aspect, and their role in pharmacological applications. Databases used to search for literature mostly rely on the Plant List, SCI-Finder, Google Scholar, the Web of Science, Scopus, Hindawi, Bentham Science, Science Direct, PubMed, Chemical Abstracts, ACS journals, Springer, Taylor Francis, Wiley Online Library, Thieme Medical Publishers, and IOP Science.


## 2. Botanical Description

(i)Nomenclature: According to a database of the Plant List (www.Theplantlist.org, 2019), the following acceptable names of thirteenMiliusa species were listed at a level of high confidence:M. balansae Finet & Gagnep.,M. bannaensis X.L. Hou,M. brahei (F. Muell.) Jessup,M. glochidioides Hand.-Mazz.,M. horsfieldii (Bennett) Baill. ex Pierre,M. indica Lesch. ex A.DC.,M. macropoda Miq.,M. prolifica (Chun & F.C. How) P.T. Li,M. sclerocarpa (A.DC.) Kurz,M. sinensis Finet & Gagnep.,M. tenuistipitata W.T. Wang,M. traceyi Jessup, andM. velutina (A.DC.) Hook.f. & Thomson [15].Besides known nineteen Thai species, from morphological point of view, seven new species were found in Thailand:M. fragrans Chaowasku & Kessler sp. nov.,M. hirsuta Chaowasku & Kessler sp. nov.,M. intermedia Chaowasku & Kessler sp. nov.,M. nakhonsiana Chaowasku & Kessler sp. nov.,M. sessilis Chaowasku & Kessler sp. nov.,M. thailandica Chaowasku & Kessler sp. Nov, andM. umpangensis Chaowasku & Kessler sp. nov. [16]. By using DNA-barcoding analysis and the morphological comparisons with the two speciesM. pumilaChaowasku andM. filipes Ridl.,M. chantaburianaDamthongdee & Chaowasku was recorded as a new species, growing in Bangkok, Thailand [17]. In the same way, an allied member ofM. indica Leschen, namedM. jainiiGoel at Sharma, sp. nov., was discovered in South Andaman, India, and three new species,M. cambodgensis sp. nov.,M. astiana, andM. ninhbinhensis spp. nov., were reported to grow in Cambodia and Vietnam, respectively [3, 18].(ii)Phylogeny: GenusMiliusa belongs to the tribe Miliuseae of the subfamily Malmeoideae of the pantropical family Annonaceae [16, 19]. Plants of this genus established a close relationship with two genera,Hyalostemma Wall andSaccopetalum Benn., and a distinguishing feature between them can be the different number of ovules (Hyalostemma only one,Miliusa two, andSaccopetalum more than two) [19].(iii)General morphology: The plants exist in shape of shrub or tree (up toca. 40 m high). The wood appeared yellow when fresh but became darker on exposure; the parenchyma was in fine tangential lines, forming a network with the narrow to moderately broad to broad rays. The mature leaf inM. horsfieldii, for instance, indicated elliptic to ovate shape [19].Miliusaspecies have also been shown to be associated with the following characteristics: equally sized sepals and outer petals both of which are much smaller than the inner petals, a densely hairy torus, miliusoid stamens, i.e. stamens without conspicuously dilated connective tissue covering the thecae, and four part-lamellate ruminations of the endosperm [16].(iv)Distribution: GenusMiliusa, until now, has been reported to consist of about 60 species [17], distributed throughout India and Bhutan to Australia and New Guinea, but mostly found in mainland Asia [19].


## 3. Phytochemical Investigation

Nowadays, the methods and the processes of the isolation and elucidation of naturally occurring compounds from the medicinal plants have received heavy supports from the modern techniques, such as high performance liquid chromatography (HPLC), gas chromatography-mass spectrum (GC-MS), nuclear magnetic resonance (NMR), ultraviolet-visible (UV-Vis), infrared (IR), optical rotation (OR), and circular dichroism (CD) spectroscopies [1, 20]. We, herein, set out an updated phytochemical account of all isolated metabolites fromMiliusa species, principally based on chromatographic procedures. Many works have been carried out on the phytochemical investigations of several parts of ten plants, namely,M. balansae,M.CF.banacea,M. cuneata,M. fragrans,M. mollis,M. sinensis,M. smithiae,M. thorelii,M. umpangensis, andM. velutina [4, 7, 21–26]. Two hundred twenty secondary metabolites were recorded and presented in Table 1 and Figures 1–9. The names of the isolated compounds have been prepared following the arrangement of alphabetical words. In addition, Table 2 indicated a list of main essential oils from five studied species:M. baillonii,M. brahei,M. horsfieldii,M. traceyi, andM. sinensis [27–29]. Isolated metabolites ofMiliusa species were classified into a wide range, including alkaloids, geranylated homogentisic acids, flavonoids, lignans and neolignans, acetogenins, styryls, mono-phenols, terpenoids, amines and amides, alcohols, furans, and other types. The first group of thirty-two compounds1-32 was referred to as alkaloids [4, 7, 21–26]. Forty-one metabolites from compound33 to compound73 could be conveniently classified into the group of homogentisic acid derivatives [7, 13, 14, 30–34]. The structures74-116 were recognized to be flavonoids [7, 8, 11, 25, 30, 33, 35–38]. Lignans and neolignans were also found in the plants of genusMiliusa and were actually described by the state of next compounds117-144 [7, 9, 10, 24]. Due to the remarkable features, the serial compounds145-158 were assignable to the group of acetogenin derivatives [5, 32, 38–40]. Ten compounds159-168 can be seen as lactones [11, 38], and eight constituents169-176 belonged to styryl derivatives [31, 32, 38, 41]. Terpenoids included the structures177-185 [11, 25, 37, 42]. The reports of mono-phenols and their glycosides fromMiliusa species are now available elsewhere, but, herein, they were summed up in a total of thirteen compounds186-198 [11, 24, 30, 32, 42]. Six amines and amides199-204 [7, 8, 26], six alcohols205-210 [11], three aldehydes type furfurals211-213 [32], and last compounds214-220 [25, 26, 32, 41] have been identified as the remaining metabolites present in genusMiliusa.Table 1
Chemical constituents fromMiliusa species.
No Compounds Species References Alkaloids 1 Asimilobine M. mollistwig [24] 2 Coclaurine M. balansae stem [26] 3 Dehydroxylopine M. cuneatastem and leaf [21] 4 1,9-Dihydroxy-2,11-dimethoxy-4,5-dihydro-7-oxoaporphine M. cuneatastem and leaf [21] 5 2,10-Dimethoxy-3,11-dihydroxy-5,6-dihydroprotoberberine M. cuneatastem and leaf [21] 6 N,O-Dimethylharnovine M. cuneatastem and leaf [21] 7 10-Hydroxyliriodenine M. CF. banacearoot [4] 8 Isocorydine M. velutinastem bark [23] 9 (+)- Isocorydineα-N-oxide M. velutinastem bark [22] 10 Kinabaline M. cuneatastem and leaf [21] 11 Lanuginosine M. cuneatastem and leaf [21] 12 Liriodenine M. balansae stem;M. cuneatastem and leaf; M. mollistwig, M. sinensis leaf and branch; M. velutinastem bark [21, 23–26, 37] 13 (+)-Liriotulipiferine M. cuneatastem and leaf [21] 14 10-Methoxyliriodenine (lauterine) M. CF. banacearoot [4] 15 1-N-Methylcoclaurine M. balansae stem [26] 16 N-Methylcorydaldine M. cuneatastem and leaf [21] 17 N-Methyllindcarpine M. cuneatastem and leaf [21] 18 Miliusacunine A M. cuneata leaf [7] 19 Miliusacunine B M. cuneata leaf [7] 20 Miliusacunine C M. cuneata leaf [7] 21 Miliusacunine D M. cuneata leaf [7] 22 Miliusacunine E M. cuneata leaf [7] 23 Miliusathorine A M. thoreliistem and root [8] 24 Miliusathorine B M. thoreliistem and root [8] 25 Norcorydine M. velutinastem bark [23] 26 (-)-Nordicentrine M. cuneatastem and leaf [21] 27 Norisocorytuberine M. cuneatastem and leaf [21] 28 (−)-Norushinsunine M. mollistwig; M. thoreliistem and root [8, 24] 29 Pseudocolumbamine M. cuneatastem and leaf [21] 30 Reticuline M. velutinastem bark [23] 31 Salutarine M. cuneatastem and leaf [21] 32 Wilsonirine M. cuneatastem and leaf [21] Homogentisic acid derivatives 33 Methyl 2-(1′β-geranyl-5′β-hydroxy-2′-oxocyclohex-3′-enyl) acetate M. umpangensis leaf; M. velutinafruit [32, 33] 34 2-(1′β-Geranyl-5′β-hydroxy-2′-oxocyclohex-3′-enyl) acetic acid M. velutinafruit and flower [32] 35 Miliusanal M. velutinafruit [32] 36 Miliusanone A M. velutinafruit [32] 37 Miliusanone B M. velutinafruit [32] 38 Miliusanone C M. velutinaflower [32] 39 Miliusanone D M. velutinaflower [32] 40 (+)-Miliusate M. balansae leaf, branch and stem; M. sinensis leaf, twig and flower; M. umpangensis leaf [13, 14, 31, 33, 34] 41 (+)-Miliusane I M. balansae stem; M. sinensis leaf, twig and flower; M. umpangensisleaf [13, 14, 33] 42 (+)-Miliusane II M. balansae stem; M. sinensis leaf, twig and flower [13, 14] 43 (+)-Miliusane III M. sinensis leaf, twig and flower [14] 44 (+)-Miliusane IV M. sinensis leaf, twig and flower [14] 45 (+)-Miliusane V M. sinensis leaf, twig and flower [14] 46 (+)-Miliusane VI M. sinensis leaf, twig and flower [14] 47 (+)-Miliusane VII M. sinensis leaf, twig and flower [14] 48 (+)-Miliusane VIII M. sinensis leaf, twig and flower [14] 49 (+)-Miliusane IX M. balansae stem; M. sinensis leaf, twig and flower [13, 14] 50 (+)-Miliusane X M. sinensis leaf, twig and flower [14] 51 (+)-Miliusane XI M. sinensis leaf, twig and flower [14] 52 (+)-Miliusane XII M. sinensis leaf, twig and flower [14] 53 (+)-Miliusane XIII M. sinensis leaf, twig and flower [14] 54 (+)-Miliusane XIV M. balansae stem; M. Sinensis leaf, twig and flower [13, 14] 55 (+)-Miliusane XV M. balansae stem; M. Sinensis leaf, twig and flower [13, 14] 56 (+)-Miliusane XVI M. sinensis leaf, twig and flower [14] 57 (+)-Miliusane XVII M. balansae stem; M. sinensis leaf, twig and flower [13, 14] 58 (+)-Miliusane XVIII M. sinensis leaf, twig and flower [14] 59 (+)-Miliusane XIX M. sinensis leaf, twig and flower [14] 60 (+)-Miliusane XX M. sinensis leaf, twig and flower [14] 61 Miliusane XXI M. balansae stem [13] 62 Miliusane XXII M. balansae stem [13] 63 Miliusane XXIII M. balansae stem [13] 64 Miliusane XXIV M. balansae stem [13] 65 Miliusane XXV M. balansae stem [13] 66 Miliusane XXVI M. balansae stem [13] 67 Miliusane XXVII M. balansae stem [13] 68 Miliusane XXVIII M. balansae stem [13] 69 Miliusane XXIX M. balansae stem [13] 70 Miliusane XXX M. balansae stem [13] 71 Miliusane XXXI M. balansae stem [13] 72 (+)-Miliusol M. balansaeleaf, stem and branch; M. cuneataleaf, M. sinensis leaf, twig and flower; M. umpangensisleaf [7, 13, 14, 24, 30] 73 Miliusolidea M. balansae leaf and branch [30] Flavonoids Flavones 74 Artemetin M. thoreliileaf [8] 75 Ayanin (5,3′-dihydroxy-3,7,4′-trimethoxyflavone) M. smithiae leaf and twig;M. umpangensis leaf [33, 36] 76 Chrysosplenol B (chrysoplenetin) M. balansae leaf and branch;M. cuneata twig [7, 35] 77 Chrysosplenol C M. balansae leaf and branch [11, 30, 35] 78 Chrysosplenol D M. umpangensis leaf [33] 79 3,5-Dihydroxy-7,3′,4′-trimethoxyflavone M. sinensis leaf and branch [25, 37] 80 6,4′-Dihydroxy-3,5,7-trimethoxyflavone M. thoreliistem and root [8] 81 Dimethylmikanin M. thoreliistem and root [8] 82 3,5,6,7,3′,4′-Hexamethoxyflavone M. thoreliileaf [8] 83 5-Hydroxy-3,7-dimethoxy-3′,4′-methylenedioxyflavone M. cuneata leaf and twig; M. thoreliistem, root and leaf [7, 8] 84 5-Hydroxy-3,7,4′-trimethoxyflavone M. smithiae leaf and twig [36] 85 5-Hydroxy-3,6,7,4′-tetramethoxyflavone M. thoreliistem and root [8] 86 4′-Hydroxy-3,5,6,7-tetramethoxyflavone M. thoreliistem and root [8] 87 4′-Hydroxy-3,5,7,3′-tetramethoxyflavone M. cuneata leaf [7] 88 Isokanugin M. thoreliileaf [8] 89 3-O-Methylkaempferol M. thoreliistem and root [8] 90 Melisimplexin M. thoreliistem, root and leaf [8] 91 Melisimplin M. thoreliileaf [8] 92 Miliufavol M. balansae leaf and branch [35] 93 Miliusathorone M. thoreliistem and root [8] 94 Ombuine M. balansae leaf and branch; M. umpangensis leaf [33, 35] 95 Pachypodol M. balansae leaf and branch; M. cuneata leaf and twig; M. thoreliileaf [7, 8, 35] 96 3,5,7,3′,4′-Pentamethoxyflavone M. thoreliistem, root and leaf [8] 97 Quercetagetin-3,5,7-trimethyl ether M. thoreliistem and root [8] 98 Quercetagetin-3,5,7,3′-tetramethyl ether M. thoreliistem and root [8] 99 Quercetin-3-O-methyl ether M. thoreliistem and root [8] 100 Quercetin-3,7-dimethyl ether M. thoreliistem and root;M. umpangensis leaf [8, 33] 101 Quercetin-3,5,3′-trimethyl ether M. thoreliistem and root [8] 102 Retusin M. thoreliistem and root [8] 103 Rhamnetin M. velutinaleaf [38] 104 Rutin M. balansae leaf; M. umpangensis leaf [11, 33] 105 7,3′,4′-Trimethylquercetin M. umpangensis leaf [33] Chalcones 106 2′,6′-Dihydroxy-4′-Methoxydihydrochalcone M. balansae leaf and branch [31] 107 4′,6′-Dihydroxy-2′,3′,4-trimethoxydihydrochalcone M. sinensis leaf and branch [37] 108 Dihydropashanone M. balansae leaf and branch; M. sinensisleaf and branch [25, 31, 37] 109 Pashanone M. sinensis leaf and branch [6, 25, 37] Flavanones 110 5-Hydroxy-6,7-dimethoxyflavanone (onysilin) M. balansae leaf and branch; M. sinensis leaf and branch [6, 25, 31, 37] 111 5-Hydroxy-7,8-dimethoxyflavanone M. balansae leaf and branch; M. sinensis leaf and branch [25, 31, 37] 112 5-Hydroxy-7-methoxyflavanone (pinostrobin) M. balansae leaf and branch; M. sinensis leaf and branch [25, 31, 37] 113 5-Hydroxy-7,4′-methoxyflavanone M. balansae leaf and branch; M. sinensis leaf and branch [25, 31, 37] 114 7-O-Methyleriodictyol M. velutinaleaf [38] 115 Sakuranetin M. velutinaleaf [38] Flavan 116 (−)-Epicatechin M. balansae leaf; M. fragrans leaf and stem;M. mollis leaf [9, 11, 24] Lignans and neolignans Lignans 117 (+)-3-Hydroxyveraguensin M. fragransstem [9] 118 (7S,8S,7′R,8′S)-3,4,5,3′,4′-Pentamethoxy-7,7′-epoxylignan M. fragransstem [9] 119 (+)-Syringaresinol M. cuneata leaf [7] 120 Veraguensin M. fragransstem [9] Neolignans 121 2-(4-Allyl-2,6-dimethoxyphenoxy)-1-(3,4-dimethoxyphenyl)propane M. mollisleaf [9] 122 Conocarpan M. mollis twig [24] 123 Decurrenal M. mollisleaf [10] 124 (+)-3-O-Demethyleusiderin C [(7S,8R)-Δ8′-3-hydroxy-4,5,5′-trimethoxy-7.O.3′,8.O.4′-neolignan] M. fragransleaf [9] 125 (+)-4-O-Demethyleusiderin C [(7S,8R)-Δ8′-4-hydroxy-3,5,5′-trimethoxy-7.O.3′,8.O.4′-neolignan] M. fragransleaf and stem [9] 126 (2R,3R)-2,3-Dihydro-2-(4-hydroxy-3-methoxyphenyl)-3-methyl-5-(E)-propenylbenzofuran M. mollis twig [24] 127 (2S,3S)-2,3-Dihydro-2-(4-methoxyphenyl)-3-methyl-5-[1(E)-propenyl] benzofuran M. mollis twig [24] 128 (+)-Eusiderin A M. fragransstem [9] 129 Eusiderin C M. fragransstem [9] 130 Eusiderin D M. fragransstem and leaf [9] 131 Licarin A M. fragransleaf [9] 132 (7S,8S)-threo-Δ8′-4-Methoxyneolignan M. mollis twig [24] 133 7-Methoxymiliumollin [(2R,3R)-5-allyl-2,3-dihydro-2-(4-hydroxyphenyl)-7-methoxy-3-methylbenzofuran] M. mollisleaf [10] 134 3′-Methoxymiliumollin [(2R,3R)-5-allyl-2,3-dihydro-2-(4-hydroxy-3-methoxyphenyl)-3-methylbenzofuran] M. mollisleaf [10] 135 (−)-4-O-Methylmiliusfragrin [(7R,8R)-Δ8′-3,4,5′-trimethoxy-7.O.3′,8.O.4′-neolignan] M. fragransstem [9] 136 4′-O-Methylmiliumollin [(2S,3S)-5-allyl-2,3-dihydro-2-(4-methoxyphenyl)-3-methylbenzofuran)] M. mollisleaf [10] 137 (−)-Miliufragranol A [(Δ7′-9′-hydroxy-3,4,3′,5′-tetramethoxy-8.O.4′-neolignan] M. fragransstem [9] 138 (−)-Miliufragranol B [(Δ8′-4-hydroxy-3,5′-dimethoxy-8.O.4′-neolignan] M. fragransleaf [9] 139 (−)-Miliusfragrin [(7R,8R)-Δ8′-4-hydroxy-3,5′-dimethoxy-7.O.3′,8.O.4′-neolignan] M. fragransleaf and stem [9] 140 Miliumollin [(2R,3R)-5-allyl-2,3-dihydro-2-(4-hydroxyphenyl)-3-methylbenzofuran)] M. mollisleaf [10] 141 Miliumollinone [(2R,3R)-2,3-dihydro-2-(4-hydroxyphenyl)-3-methyl-5-(2-oxopropyl)-benzofuran] M. mollisleaf [10] 142 Miliusanollin [(7R,8R)-threo-Δ8′-7-acetoxy-4-methoxy-8-O-4′-neolignan] M. mollisleaf [10] 143 (7S,8R)-7-hydroxy-3,4,3′-trimethoxy-Δ1,3,5,1′,3′,5′,8′-8.O.4′-neolignan M. fragransleaf [9] 144 Virolongin B M. fragransstem [9] Acetogenins 145 Acetogenins A M. velutinastem bark [5] 146 Acetogenins B M. velutinastem bark [5] 147 Cananginone A M. velutinastem bark and flower [32, 40] 148 Cananginone B M. velutinastem bark [40] 149 Cananginone C M. velutinastem bark [40] 150 Cananginone D M. velutinastem bark [40] 151 Cananginone E M. velutinastem bark [40] 152 Cananginone F M. velutinastem bark [40] 153 Cananginone G M. velutinastem bark [40] 154 Cananginone H M. velutinastem bark, leaf and flower [32, 38, 40] 155 Cananginone I M. velutinastem bark [40] 156 Miliusolidea M. velutinastem bark [39] 157 Miliusolide dihydro derivative M. velutinastem bark [39] 158 Goniothalamusin M. velutinastem bark [5] Lactones 159 Curcolide M. balansae leaf [11] 160 Serralactone M. balansae leaf [11] 161 Velutinone A M. velutinaleaf [38] 162 Velutinone B M. velutinaleaf [38] 163 Velutinone C M. velutinaleaf [38] 164 Velutinone D M. velutinaleaf [38] 165 Velutinone E M. velutinaleaf [38] 166 Velutinone F M. velutinaleaf [38] 167 Velutinone G M. velutinaleaf [38] 168 Velutinone H M. velutinaleaf [38] Styryls Mono-styryl derivatives 169 3,4-Dimethoxy-6-styryl-pyran-2-one M. balansae leaf and branch [31] 170 (2E,5E)-2-Methoxy-4-oxo-6-phenyl-hexa-2,5-dienoic acid methyl ester M. balansae leaf and branch [31] 171 Yangonin M. velutinaleaf, fruit and flower [32, 38] Bi-styryl derivatives 172 Miliubisstyryl A M. balansae leaf and branch [41] 173 Miliubisstyryl B M. balansae leaf and branch [41] 174 Velutinindimer A M. velutinaleaf, fruit and flower [32, 38] 175 Velutinindimer B M. velutinaleaf, fruit and flower [32, 38] 176 Velutinindimer C M. velutinaleaf [38] Terpenoids Norsesquiterpenoids type megastigmanes and megastigmane glycosides 177 Alangionoside B M. balansaestem [42] 178 Ampelopsisionoside M. balansae leaf [11] 179 Milbaside A M. balansae leaf [11] 180 Milbaside B M. balansae leaf [11] 181 Milbaside C M. balansae leaf [11] 182 Miliusoside C M. balansaestem [42] 183 Myrsinionoside A M. balansae leaf [11] 184 Myrsinionoside D M. balansae leaf [11] Triterpenoid 185 24-Methylencycloartane-3β,21-diol M. sinensis leaf and branch [25, 37] Mono-phenols and mono-phenol glycosides 186 bis(2-Hydroxyphenyl)methyl ether M. balansae leaf and branch [30] 187 Cuchiloside M. balansaestem [42] 188 4-Hydroxybenzonitrile M. velutina fruit [32] 189 4-Hydroxybenzaldehyde M. velutina fruit [32] 190 Icariside D2 M. mollis twig [24] 191 Isovanillin M. velutina fruit [32] 192 1-(3-Methylbutyryl)phloroglucinol-glucopyranoside M. balansae leaf [11] 193 Miliusoside A M. balansaestem [42] 194 Miliusoside B M. balansaestem [42] 195 Osmanthuside H M. balansaestem [42] 196 1-(α-L-Rhamnosyl-(1→6)-β-D-glucopyranosyloxy)-3,4,5-trimethoxybenzene M. balansaestem [42] 197 3,4,5-Trimethoxyphenol-β-D-glucopyranoside M. balansaestem [42] 198 Tyrosol-1-O-β-xylopyranosyl-(1→6)-O-β-glucopyranoside M. mollis twig [24] Amines and amides 199 Adenine riboside M. balansae stem [26] 200 Allantoin M. balansae stem [26] 201 N-trans-Caffeoyltyramine M. cuneata twig; M. thoreliistem and root [7, 8] 202 N-trans-Coumaroyltyramine M. cuneata twig [7] 203 N-trans-Feruloyltyramine M. cuneata twig; M. thoreliistem and root [7, 8] 204 Uridine M. balansae stem [26] Alcohols 205 β-D-Glucopyranoside (Z)-3-hexenol M. balansae leaf [11] 206 erythro-Guaiacylglycerol M. balansae leaf [11] 207 threo-Guaiacylglycerol M. balansae leaf [11] 208 (L)-Guaiacyl glycerol 2′-O-β-D-glucopyranoside M. balansae leaf [11] 209 erythro-1-C-Syringylglycerol M. balansae leaf [11] 210 threo-1-C-Syringylglycerol M. balansae leaf [11] Furfurals 211 5-Acetyloxymethylfurfural M. velutina fruit [32] 212 5-Hydroxymethylfurfural M. velutina fruit [32] 213 5-Methoxyfurfural M. velutina fruit [32] Others 214 D-​Glucose M. balansae stem [26] 215 Octacosanoic acid M. balansae leaf and branch [41] 216 β-Sitosterol M. balansaestem; M. velutina fruit [26, 32] 217 β-Sitosterol glucoside M. balansaestem;M. sinensis leaf and branch [25, 26] 218 Sodium benzoate M. balansae leaf and branch [30] 219 Stigmasterol M. sinensis leaf and branch; M. velutina fruit and flower [25, 32] 220 Sucrose M. balansae stem [26] T h e   a coincidence nameTable 2
Essential oils from presentativeMiliusaspecies.
Species Collections Part Uses Main constituents References M. baillonii Quang Binh-Vietnam Fresh leaf Naphthalene (1.0%), bicycloelemene (1.1%), germacrene B (1.2%), germacrene D (1.2%),δ-cadinene (1.4%), isolongifolene (1.2%), spathulenol (1.4%), α-terpinolene (1.5 %), elemol (1.7%), linalool (2.7%), β-elemene (3.5%), τ-muurolol (3.8%), α-humulene (6.2%), β-caryophyllene (10.6%), and Z-citral (41.2%) [28]  M. sinensis Nghean-Vietnam Dried leaf (E)-β-Ocimene (2.4%), aromadendrene (6.6%), β-elemene (7.1%), α-humulene (7.9%) and β-caryophyllene (19.5%) [29]  M. brahei 16°31’S, 145°28’EQueensland-Australia Leaf Cubeban-11-ol (1.0%), caryophyllene oxide (1.1%),α-copaene (1.2%), α-selinene (1.2%), viridiflorene (1.2%), δ-cadinene (1.8%), viridiflorol (1.8%), β-selinene (2.2%), geraniol (2.3%), (Z)-β-ocimene (2.6%), aromadendrene (3.0%), globulol (3.3%),α-terpineol (3.5%), spathulenol (3.6%), germacrene D (5.3%), linalool (7.4%), α-humulene (11.3%), β-caryophyllene (12.8%) and bicyclogermacrene (12.9%) [27]  M. horsfieldii 13°48’S, 143°28’EQueensland-Australia Leaf Geraniol (1.0%), globulol (1.2%), cubeban-11-ol (1.3%), bicycloelemene (1.8%),α-cadinol (1.9%), allo-aromadendrene (1.9%), viridiflorene (2.5%), bicyclogermacrene (2.5%), α-selinene (2.6%), β-selinene (2.8%), δ-cadinene (3.0%), α-humulene (3.4%), linalool (3.8%), α-copaene (7.5%), caryophyllene oxide (12.5%) and β-caryophyllene (20.2%), [27]  M. traceyi 14°00’S, 143°19’EQueensland-Australia Leaf δ-Cadinene (1.8%), α-humulene (2.4%), spathulenol (2.9%), limonene (3.0%), bicyclogermacrene (3.8%), germacrene D (4.9%), β-caryophyllene (13.5%), β-pinene (18.6%) and α-pinene (18.7%) [27]Figure 1
Alkaloids fromMiliusa species.Figure 2
Geranylated homogentisic acid derivatives fromMiliusa species and their plausible biogenetic pathway.Figure 3
Flavonoids fromMiliusa species.Figure 4
Lignans and neolignans fromMiliusa species.Figure 5
Acetogenins and lactones fromMiliusa species.Figure 6
Styryls fromMiliusa species.Figure 7
Terpenoids fromMiliusa species.Figure 8
Mono-phenols, amines, amides, alcohols, and furans fromMiliusa species.Figure 9
Other types fromMiliusaspecies.


### 3.1. Alkaloids

With natural product substances, alkaloidal compounds were famous long ago. The proportion of alkaloids has been found to deeply depend on the typical parts of the plants and environmental effects. For example, Aniszewski (2007) suggested that a large percentage of alkaloids reached up to 10-25% from the higher plants [1].Miliusa species also provide a rich alkaloidal source. Up to now, over thirty alkaloidal constituents1-32 were recorded, involved in the previous phytochemical investigations on several plants,M. balansae,M.CF.banacea,M. mollis,M. sinensis,M. thorelii, andM. velutina, but mostly found inM. cuneata(Figure 1) [4, 7, 21–26, 37]. Among them, eleven constituents, namely, compounds4-5,7,9, and18-24, were new in nature. Liriodenine (12) was likely to be familiar with plants from genusMiliusa and widely distributed inM. balansae stem,M. cuneatastem and leaf,M. mollistwig,M. sinensis leaf and branch, andM. velutinastem bark [21, 23–26, 37]. With the exception of new compounds and two known others,12 and28, it was remarked that the remaining compounds were isolated from this genus for the first time.Miliusa alkaloids can be found in formulating a variety of main skeletons, such as aporphine and oxo-aporphine backbones in respective asimilobine (1) and 10-hydroxyliriodenine (7), tetrahydroisoquinoline and quinolone in respective coclaurine (2) and N-methylcorydaldine (16), azafluorenone in kinabaline (10), dihydroprotoberberine and oxo-protoberberine in respective 2,10-dimethoxy-3,11-dihydroxy-5,6-dihydroprotoberberine (5) and miliusacunine A (18), benzylisoquinoline in reticuline (30), or morphinan in salutarine (31).Taking the newly isolated alkaloids into consideration, two new oxo-aporphine and dihydroprotoberberine alkaloids4-5, in addition to thirteen known others (Table 1), were obtained from 95% ethanol extract of air-dried and powdered stem and leaf ofM. cuneata [21]. One of the immensely value aspects of 2,10-dimethoxy-3,11-dihydroxy-5,6-dihydroprotoberberine (5) is that this compound possessed the positive and negative charges in nitrogen and oxygen atoms, respectively [21]. Khan and Kumar (2015) suggested that alkaloids with bipolar charges had a tendency to bind to the serum proteins better than that of neutral compounds [43].Following the outcomes in the isolation and NMR-structural elucidation, 10-methoxyliriodenine (14) was a known alkaloid, but its 10-hydroxylated derivative7 was determined to be a new oxo-aporphine alkaloid in nature; both of these two compounds were precipitated out of the MeCOEt extract (2.8 g) ofM. CF.banacea species [4]. Likewise, isocorydine (8), especially its new unusual derivative (+)-isocorydine α-N-oxide (9), has successfully been separated from extracts ofM. velutina stem bark [22, 23].An additional significance in phytochemical works related to plants is that the leaf ofM. cuneata species is likely to be a rich source of oxo-protoberberine alkaloids. In 2005, five new alkaloids of type oxo-protoberberine were isolated from the acetone extract ofM. cuneataleaf, trivially named miliusacunines A-E (18-22) [7].Finally, three alkaloids, consisting of two new dihydro-oxo-protoberberine derivatives miliusathorines A-B (23-24) and known one (−)-norushinsunine (28), have been purified from the combined extract between stem and root ofM. thorelii species [8].


### 3.2. Geranylated Homogentisic Acid Derivatives

Phenolic acids of type homogentisic acids are usually detected in both terrestrial plants and bacterial pathogenic strains [44, 45]. Homogentisic acids indicated the significant antioxidant and anti-inflammatory capacities, but the excess accumulation of these can cause “alkapton” symptom in the human body [45, 46].Considerable attention should be paid to the novel class of geranylated homogentisic acid derivatives from plants of genusMiliusa. Among the total forty-one isolated compounds33-73, secondary metabolites40-73 were novel and relatively rare compounds in nature while a number of isolates35-39 were new in literature.General features were highlighted in the chemical structures33-34 and36-72; that is, carbonylation and geranylation often occurred at carbons C-2 (or C-2′) and C-1 (or C-1′), respectively (Figure 2). Furthermore, double bonds might be located at carbons C-3 and C-4 (or C-3′ and C-4′); hydroxylation, methoxylation, or acetoxylation was normally observed at carbon C-5 (or C-5′).Of isolated compounds40-72, most of these unique structures might possibly be formed by a rare C-18 skeleton, containing a characteristic γ-lactone spiro-ring system. Five-member γ-lactone ring were geranylated in the structures40-57,61-67, and72, but were found to be opened in the structures58-60 and68-71. Two isolated compounds59-60 also contained a tetrahydrofuran ring. Additionally, the combination of NOE effect observations, Mosher reactions, and X-ray measurements allowed for determining the absolute configuration, in which 1R,5S,1′R-form and 5β-orientation were suitable for the group of compounds40-72 [14]. C13-NMR provided the evidence of chemical shifts δC, thereby showing that, at carbons C-1, C-5, and C-1′ of compounds containing spiro-ring system, δC reachedca. 52.0-56.0 ppm,ca. 63.0-68.0 ppm, andca. 26 ppm, respectively.As part of an interdependent work, more recently, Promgool et al. (2019) reported that chromatographic separation of extracts ofM. velutinafruit and flower has resulted in isolating and elucidating five new rare geranylated homogentisic acid derivatives, miliusanal (35) and miliusanones A-D (36-39), in addition to known ones, methyl 2-(1′β-geranyl-5′β-hydroxy-2′-oxocyclohex-3′-enyl) acetate (33) and 2-(1′β-geranyl-5′β-hydroxy-2′-oxocyclohex-3′-enyl) acetic acid (34) [32]. New compound35 indicated the property of a phenolic aldehyde with CHO (δC 196.1 ppm in solvent CDCl3), whereas new compounds38-39 were significantly made of 6′′-hydroxylated groups (δC 75.6-77.4 ppm in solvent CDCl3 + CD3OD).Novel (+)-miliusate (40) was one of the interesting constituents of Vietnamese plantM. balansae [31]. After that, it was reported appearing in two other species:M. sinensisleaf, twig and flower, andM. umpangensis leaf [14, 19, 33, 34]. So far, the methanol-water extract (95:5, v/v) of Vietnamese plantM. balansae leaf and branch has shown to comprise one novel compound, (+)-miliusol (72), and one new natural product, miliusolide (73) [30]. In NOE interactions H-3a to H-5 and H-7a were key evidence to determine these three protons with orientedcis-shape and the absolute configuration was established as 3aS,5S,7aRin compound73.Novel geranylated homogentisic acids derivedMiliusa plants were more commonly referred to by their trivial name. By using Table 1 and Figure 2, we continue to make comments relating to a serial number of (+)-miliusanes I-XXXI (41-71). Secondary metabolites41-60 were separated from dichloromethane extract of the other Vietnamese plantM. sinensisleaf, twig, and flower, whereas the remaining members61-71, once again, derived fromM. balansae species [13, 14]. As shown in Figure 2, the plausible biogenetic pathway explained why these compounds were classified as geranylated homogentisic acids, in which the first step involved the combination between precursor homogentisic acid and geranyl unit of geranyl diphosphate (geranyl PP). Obviously, the methylation of intermediate productA produced compound53 while lactone ring-cyclization and dehydrate applied toA would give72; compound53 was then joined to epoxide ring-cyclization reaction and dehydrated to form59 [14].Taken together, serial compounds40-72 were useful biomarkers for either genusMiliusa or family Annonaceae, and they also accounted for the close relationship between the two speciesM. balansaeandM. sinensis.


### 3.3. Flavonoids

Now we do take a point of crucial information in mentioning another class ofMiliusa metabolites. Phytochemical investigations onMiliusa species also proved the existence of flavonoids. Flavonoids were detected in leaf, twig, branch, stem, or root of nine plants:M. balansae,M. cuneata,M. fragrans,M. mollis,M. sinensis,M. smithiae,M. thorelii,M. umpangensis, andM. velutina, to date (Table 2). Herein, we draw a list of forty-three isolated compounds74-116 fromMiliusa species. Chemical index also exhibited thatMiliusaflavonoids can be divided into several main groups: flavonols74-105, chalcones106-109, flavanones110-115, and flavan116 (Table 1 and Figure 3) [7, 8, 11, 25, 30, 33, 35–37]. More than thirty flavonols were found but flavones and isoflavones were absent, to the best of our knowledge. Likewise, flavanones and isoflavanones have not been recorded yet.The most important information to be gained from structural features is that isolated flavonoids derived fromMiliusa species were generated asmono-flavonoid derivatives. The phenomenon of methoxylation occurred at carbon C-3 of most isolated flavonols. Normally, flavonols and flavanones were associated with substituents at carbons C-5, C-6, C-7, C-8, C-3', and C-4' by hydroxy and methoxyl groups.Despite the fact that the known flavonoids74,77-82,84-91,96-99,101-103,105-107,109, and114-115 are abundant in the plant kingdom, these compounds were reported fromMiliusa species for the first time. Rutin (104) was recognized to be only flavonol glycoside isolated from plants of genusMiliusa. In the meantime, (−)-epicatechin (116) was also a unique flavan to be found.M. thorelii species seemed to be a rich supply of flavonols. Bioguided assay and fractionation of extracts of leaf, stem, and root afforded one new natural product, miliusathorone (92), in addition to nineteen known ones,74,80-83,85-86,88-91, and95-102 [8]. New metabolite92 had the characteristic remark with chemical shifts of -O-CH2-O- [δH 6.06, δC 101.8]. Interestingly, new metabolite named miliufavol (92) was derived from methanol-water (95:5, v/v) extract of air-dried groundM. balansae leaf and branch [35], in which this compound was an uncommon flavonol by combining of pachypodol (95) and benzyl unit at carbon C-8.Four chalcone derivatives, 2′,6′-dihydroxy-4′-methoxydihydrochalcone (106), 4′,6′-dihydroxy-2′,3′,4-trimethoxydihydrochalcone (107), dihydropashanone (108), and pashanone (109), were significant constituents of the two Vietnamese plantsM. balansaeandM. sinensis [25, 31, 37]. In contrast to109, three compounds106-108 belong to dihydrochalcone, and compound107 was a new isolated compound in literature. Isolated flavanones110-113 were also considered as main components of VietnameseM. balansaeandM. sinensis, but two compounds, final derivatives 7-O-methyleriodictyol (114) and sakuranetin (115), were only detected inM. velutinaleaf up to now [38].


### 3.4. Lignans and Neolignans

We continuously provide the next phytochemical profiles of the other class of isolated compounds. Starting with the deepest aim to find biologically active molecules from genusMiliusa, four lignans117-120 and twenty-four neolignans121-144 have also been isolated (Table 1 and Figure 4). In addition, these phytochemicals from genusMiliusa originated from three parts, leaf, stem, and twig, of two main species,M. fragrans andM. mollis, but occasionally found inM. cuneataspecies [8–10, 24].It is possible to set up a clear arrangement for backbones of either lignans or neolignans.Miliusa lignans were able to form up to two main skeletons, tetrahydrofuran lignan (compounds117-118 and120) and 7,9′:7′,9-diepoxylignan (compound119). In the case of neolignans, three main scaffolds can be found, namely, 8.O.4′-neolignan (compounds121,132,137-138, and142-144), 7.O.3′,8.O.4′-neolignan (124-125,128-130,135, and139), and dihydrobenzofuran skeleton (compounds122-123,126-127,131,133-134,136, and140-141). Two skeletons of 8.O.4′-neolignan and 7.O.3′,8.O.4′-neolignan were only represented in the two Thai speciesM. fragrans andM. mollis, thereby suggesting the close relationship between them [9, 10, 24].Besides geranylated homogentisic acids, oxo-protoberberine alkaloids, and flavonols, chemical constituents ofM. cuneataleaf were also in association with the presence of the well-known lignan (+)-syringaresinol (119) [7]. In 2013, sixteen secondary metabolites, being isolated from methanol extracts of ThaiM. fragransleaf and stem in the work of Sawasdee and partners, were described as three lignans117-118,120 and thirteen neolignans121,124-125,128-131,135,137-139, and143-144 [9]. The new lignan (+)-3-hydroxyveraguensin (117) and its relatives118 and120 have been structurally established as 7S,8S,7′R,8′S-configuration (cis-H-7/H-7′,cis-H-7′/H-8′,trans-H-7/H-8, andtrans-H-8/H-8′). The new neolignans124-125,128,135, and139 and two known ones129-130 shared the same structure of three parts, 5-methoxyl-phenylpropanoid unit, 2-methyl-1,4-dioxane unit, and phenyl ring linkage to carbon C-7. However, the absolute configurations were elucidated as 7S,8R for124-125 and129-130, 7S,8Sfor128, and 7R,8Rfor135 and139, but the stereochemistry for new 8.O.4′-neolignans137-138 and their analogs138 and144 could not be determined.In the two years 2010 and 2013, Sawadee and partners provided the results of the phytochemical isolation and NMR-structural elucidation of ThaiM. mollis, in which one new neolignan of type dihydrobenzofuran (2S,3S)-2,3-dihydro-2-(4-methoxyphenyl)-3-methyl-5-[1(E)-propenyl]benzofuran (127), one new 8.O.4′-neolignan (7S,8S)-threo-Δ8′-4-methoxyneolignan (132), and two known others123 and126 were isolated from twig; five new neolignans of type dihydrobenzofuran 7-methoxymiliumollin (133), 3′-methoxymiliumollin (134), 4′-O-methylmiliumollin (136), miliumollin (140), miliumollinone (141); one new 8.O.4′-neolignan miliusanollin (142); and one known other (123) were derived from leaf [9, 10].Neolignans of type dihydrobenzofuran from Thai plants have been shown to be associated with 2R,3R-absolute configuration (trans-H-2/H-3) in groups122-123,126,133-134, and140-141 and 2S,3S-absolute configuration (cis-H-2/H-3) in127 and136, while new compound132 set up 7S,8S-model when compared to 7R,8R-model in142 and 7S,8R-model in143.


### 3.5. Acetogenins and Lactones

A bit of the attractive phytochemical outcome arose from the class of isolated acetogenins. As we know, acetogenins and their analogs are now remarkable characteristics of the family Annonaceae [47]. From Table 1 and Figure 5, isolated acetogenins existed in bark, stem bark, flower, and leaf ofM. velutina species and they were new compounds except for goniothalamusin (158). The most striking feature is that these isolated compounds were able to form up to one or two triple bonds in a long aliphatic side chain terminated by γ-hydroxy (or γ-methoxyl)-γ-lactone unit, methyl group, or double bond.Earlier phytochemical report by Jumana and coauthors (2000) showed that acetogenins A-B (145-146) obtained from BangladeshisM. velutina species reached up to 0.00154% and 0.008% of extract weight, respectively [5]. However, NMR data of long alkyl side chain of these two compounds remain unknown. Paying attention to the result of phytochemical study onn-hexane extract of ThaiM. velutinastem bark, based on repeating chromatographic columns on silica gel and sequential LiChrosorb RP-18 column techniques, we found that eight new compounds, alphabetically named cananginones A-I (147-155), have been successfully isolated as colorless viscous liquids [40]. Taking cananginone A (147) as an example, this new C23 linear olefinic acetogenin is accompanied by a variety of significant chemical shifts [(γ-methoxyl)-γ-lactone] unit established at δC 179.6 (C-1), δC 39.2 (C-2), δC 30.4 (C-21), δC 76.7 (C-22), δC 74.3 (C-23), and δC 59.5 (C-24); two double bonds and two triple bonds occurring at δC 65.1-146.6 ppm] [40]. Additionally, the positive OR value of +17.4 (c 0.206, CHCl3) evidently confirmed 2R,22S-configuration compared with that of goniothalamusin (158) [+14.6 (c 0.206, CHCl3)] [40].Miliusolide and its dihydro derivatives156-157 were also new derivatives of acetogenin detected inM. velutina stem bark [39]. Unfortunately, the trivial name ‘miliusolide’ was used for both metabolites73 and156 [30, 39].In the light of phytochemical research, Wongsa and partners (2017) continuously provided the outcome relative to ThaiM. velutina species (Figure 5) [38]. Fromn-hexane and ethyl acetate extracts of leaf of this plant, a rare class of eight bicyclic lactones with a C18 carbon backbone, trivially named velutinones A-H (161-168), were isolated. Similar to acetogenins, these compounds were collected with the physical property of colorless viscous liquids. Furthermore, they had shown the same feature in chemical structures, by which geranyl groups are located at carbon C-2a and the relative configuration at carbons C-2a and C-6a wassyn-model (2aR,6aR). In general, it is worth concluding that olefinic acetogenins with terminated γ-lactone and 2-geranylated bicyclic lactones indicated a great crucial role in chemotaxonomic aspect to recognizeM. velutina. Lactones in genusMiliusawere also found inM. balansae; the two known compounds curcolide (159) and serralactone (160) were two components of the leaf of this plant, collected from Vietnam [11].


### 3.6. Styryls

Most of secondary metabolites of interest to chemists pointed out that styryl derivatives were found in genusMiliusa. Styryls presented as the significant constituents of the two speciesM. balansae andM. velutina [31, 32, 38, 41]. As shown in Table 1 and Figure 6, the threemono-styryls169-171 and the fivebis-styryls172-176 have been updated. It is worth noting that yangonin (171) was, for the first time, reported from genusMiliusa, while the seven remaining isolates169 and172-176 were reported to be new compounds in nature.The shrub treeM. balansaeis widely distributed in Vietnam and China; chromatographic examination of the polar extract of leaf and branch of this plant yielded the two new mono-styryls 3,4-dimethoxy-6-styryl-pyran-2-one (169) and (2E,5E)-2-methoxy-4-oxo-6-phenyl-hexa-2,5-dienoic acid methyl ester (170) [31].Regarding isolated compounds of typebis-styryls, the general chemical structure was designated by cyclobutyl nucleus, while side chains were made up of phenyl rings, α-pyrone rings, and α,β-unsaturated ketones.In order to identify bioactive constituents, phytochemical investigation has been carried out on methanol-water extract (95:5, v/v) of VietnameseM. balansae leaf and branch, which continuously demonstrated the existence of two bulk newbis-styryls miliubisstyryls A-B (172-173). Although NMR data of172 were not completely assigned, the key NOE evidence proposed that the relative configurations of172 and173 were identical, beingtrans-form for H-7/H-8 and H-7′/H-8′, together withcis-form for H-8/H-7′ and H-7/H-8′.As mentioned above,M. velutinais a good reservoir of unique bicyclic lactones. From this plant, the three newbis-styryls velutinindimers A-C (174-176) were also separated [38]. According to this article, OR value approximately reached zero ([α]D +0.08 (c 0.63, MeOH-CHCl3 3:1)] and no Cotton effect was observed in CD spectrum which can be responsible for the symmetrical property of velutinindimer A (174) (compound containing a symmetrical plane). Similarly, the combination of the assignments of 1H, 13C-NMR spectroscopic signals and the correlations in 2D-NMR data, as well as the most utilization of advantageous techniques such as the CD and X-ray measurements that considered velutinindimers B-C (175-176), were two racemic compounds and the relative configurations of these compounds were 5′S,6′R,7S,8S in compound175 ([α]D +0.08 (c 0.63, MeOH-CHCl3 5:1)) and 5′R,6′S,7R,8S in compound176 ([α]D +0.03 (c 0.23, MeOH-CHCl3 9:1)).


### 3.7. Terpenoids and Phenols

M. balansae species seems to be the most crucial objective in the contents of phytochemical researches related to plants ofMiliusa species. Following the application of the variously chromatographic methods, norsesquiterpenoids of type megastigmanes,mono-phenols, and their glycosides have been determined as characteristics of genusMiliusa, especiallyM. balansae species. Eight terpenoids177-185 and thirteen phenolic compounds186-198 were summarized in Table 1 and Figure 7, which were newly isolated compounds or isolated for the first time from genusMiliusa [11, 25, 30, 32, 37, 42].Herein, mono-saccharide units of typeβ-D-glucopyranosyl parts and disaccharides units of type α-D-apiofuranosyl-(1→6)-O-β-D-glucopyranosyl, β-D-apiofuranosyl-(1→6)-O-β-D-glucopyranosyl, β-xylopyranosyl-(1→6)-O-β-D-glucopyranoside, α-L-rhamnosyl-(1→6)-β-D-glucopyranosyl moieties are glycone parts linked to aglycones of terpenoids and phenols, whereas aglycones of phenols are mostly structurally formed by phenylethanoid nucleus.Together with the one known terpenoid alangionoside B (177) and the four known phenolic glycosides cuchiloside (187), osmanthuside H (195), 1-(α-L-rhamnosyl-(1→6)-β-D-glucopyranosyloxy)-3,4,5-trimethoxybenzene (196), and 3,4,5-trimethoxyphenol-β-D-glucopyranoside (197), the phytochemical investigation of ChineseM. balansae species afforded one new megastigmane glycoside miliusoside C (182) and two newmono-phenols of type phenylethanoid glycosides miliusosides A-B (193-194) from 80% ethanol extract of dried stem [42]. The newly isolated compound182 differed from its similar structure177 in the orientation of D-apiosyl unit (α-form in182 and β-form in177).In VietnameseM. sinensisleaf and branch, 24-methylencycloartane-3β,21-diol (185) was the only triterpenoid reported to date, whereas the small-simple molecules 4-hydroxybenzonitrile (188), 4-hydroxybenzaldehyde (189), and isovanillin (191) weremono-phenols fromM. velutinafruit [25, 32, 37].Phytochemical analysis of methanol extract of VietnameseM. balansae leaf has permitted the isolation and determination of the three new megastigmane glycosides milbasides A-C (179-181), in addition to the three analogs ampelopsisionoside (178), myrsinionosides A and D (183-184), and one glucosylated phenol 1-(3-methylbutyryl)phloroglucinol-glucopyranoside (192) [11]. Structures179-181 shared the sameE-geometrical shape of double bond outside; in addition, due to the negative Cotton effect at around 240 nm (Δε ranged from –1.73 to –3.27), the absolute configurations of179-180 were 2R,3S,5S,6S, while compound181 was proposed as 3S,5R,6R(Δε245nm +3.27). In the same manner, chemical shift of methylene group ofbis(2-hydroxyphenyl) methyl ether (186) was higher than that of hydroxymethyl alcohol by 8 ppm, implying that compound186 was a new symmetrical ether [30].This review updated a phytochemical result ofM. mollis; the twig of this plant also contained the two phenolic glycosides icariside D2 (190) and tyrosol 1-O-β-xylopyranosyl-(1→6)-O-β-D-glucopyranoside (198) [24]. The highlight in phenyl ring of aglycone of new compound198 corresponded to A2B2 spin system [δH 7.10 (2H, d,J = 8.6 Hz, H-3 and H-5) and δH 6.95 (2H, d,J = 8.6 Hz, H-2 and H-6)], with glycone being remarked with two anomeric protons at δH 4.73 (1H, d,J = 7.3 Hz, H-1′) and δH 4.17 (1H, d,J= 7.6 Hz, H-1′′).


### 3.8. Amine, Amide, Alcohol Derivatives and Miscellaneous Types

A phytochemical survey conducted by Yu and partners (2009) pointed out thatM. balansae leaf, collected from China, has also been composed of one amine adenine riboside (199), and two amide allantoin (200), and uridine (204) (Figure 8) [26]. Although these compounds are now available in the natural plants, they were isolated as single compounds from genusMiliusa for the first time. Utilizing silica gel (63-200 μm) and sephadex LH-20 columns in the chromatographic isolation, three tyramine derivatives,N-trans-caffeoyltyramine (201),N-trans-coumaroyltyramine (202), andN-trans-feruloyltyramine (203), have been purified from acetone ofM.cuneata air-dried twig [7]. Since then, acetone extract ofM. thorelii stem and root was demonstrated to contain two isolates,201 and203 too [8].VietnameseM. balansae species might have been considered as a rich resource of diverse compounds. Based on the evidence of phytochemical findings and NMR explanations, six well-known alcohol derivatives,205-210, were further obtained from the leaf of this plant for the first time [11]. Among them, β-D-glucopyranoside (Z)-3-hexenol (205) was a glycosylation of longn-alkyl side chain alcohol, while the five remaining ones206-210 were categorized as two pairs oferythro andthreo isomers of glycerols and one other glucosylated glycerol. They wereerythro-guaiacylglycerol (206),threo-guaiacylglycerol (207),erythro-1-C-syringylglycerol (209),threo-1-C-syringylglycerol (210), and (L)-guaiacyl glycerol 2′-O-β-D-glucopyranoside (208), respectively. There were also records of these compounds from genusMiliusa for the first time.As can be seen, the difference of chemical components from Vietnamese and Chinese M.balansae species has been depending on geographic factor more often.Besides the presence of the rare compounds of type homogentisic acid derivatives, the ethyl acetate extract of air-driedM. velutina fruit also consisted of furfural derivatives, in which three small molecules, 5-acetyloxymethylfurfural (211), 5-hydroxymethylfurfural (212), and 5-methoxyfurfural (213), were isolated [32]. Despite the fact that these compounds were formulated with a simple pattern, they were recorded from the plants of genusMiliusa for the first time.As shown in Figure9 and Table 1, the common chemical compounds of type phytosterols can be found in severalMiliusa plants. For instance,M. balansaestem was reported to contain β-sitosterol (216), and its glucoside(217), or stigmasterol (219); this one turned out to be one of the components from bothM. sinensisleaf and branch andM. velutina fruit and flower [25, 32].Chromatographic separation of the extracts fromM. balansaestem also led to the isolation and determination of two mono-saccharide D-glucose (214) and sucrose (220) whereasM. balansaeleaf and branch were accompanied by the existence of fatty acid octacosanoic acid (215) and benzoate sodium (218) [26, 32, 41].


### 3.9. Essential Oils

For a long time, there have been researches related to essential oils, which have frequently played an important role and been regarded as a branch of either phytochemistry or pharmacological products findings [1]. Many studies focused on the applications providing multifunction in healthcare problems, alternative medicines, food and drink manufacturers, or household cleaning products. Normally, the distillation method, often by using water steam, is a prompt and efficacious way; in addition, the extractions of solvent or florasols have always been used depending on the raw materials. The systematic GC and GC-MS techniques are usually being used to identify volatile individuals.Miliusa species are also among the largest sources of this specific chemical compound. In the review of all circumstances, following the results of ethno-geographic distribution, species property, part use, extraction method, and GC-MS technical analysis, the results of studying essential oils ofMiliusa species were compiled in Table 2.Essential oils studies onMiliusaplants are quite limited. There have been only three reports to date. Among forty-six members identified from essential oils of fresh leaf of, Quang Binh, VietnameseM. baillonii species, the main constituentZ-citral reached the highest amount of 41.2% [28].M. sinensis species, collected from Nghe An, Vietnam, is also likely to be a rich resource of essential oils. From this plant, 67.1% of a total of 95.1% of essential oils were sesquiterpene hydrocarbons [29]. Significantly, α-humulene and β-caryophyllene could be seen as the main components of oils of these two VietnameseMiliusa plants (Table 2). In the same manner, the properties of plants, environmental factors, and collection time accounted for the differential components in essential oils of three, Queensland, AustralianMiliusaplants,M. brahei,M. horsfieldii, andM. traceyi [27]. As can be seen from Table 2, these three species yielded oils, in which terpenoids predominated. α-Humulene, β-caryophyllene, and bicyclogermacrene achieved more than 10% of oils ofM. brahei, while the major sesquiterpene of type caryophyllene derivatives ranged from 12% to 20%, present inM. horsfieldii oils; the highest components in oils of last plantM. traceyi encountered were the two isomers α- and β-pinene (approximately 19%). Of particular interest, β-caryophyllene was found to be one of the main compounds in all the five species (Table 2), which accounted for 10% to 20% of oils ofMiliusa species.


## 3.1. Alkaloids

With natural product substances, alkaloidal compounds were famous long ago. The proportion of alkaloids has been found to deeply depend on the typical parts of the plants and environmental effects. For example, Aniszewski (2007) suggested that a large percentage of alkaloids reached up to 10-25% from the higher plants [1].Miliusa species also provide a rich alkaloidal source. Up to now, over thirty alkaloidal constituents1-32 were recorded, involved in the previous phytochemical investigations on several plants,M. balansae,M.CF.banacea,M. mollis,M. sinensis,M. thorelii, andM. velutina, but mostly found inM. cuneata(Figure 1) [4, 7, 21–26, 37]. Among them, eleven constituents, namely, compounds4-5,7,9, and18-24, were new in nature. Liriodenine (12) was likely to be familiar with plants from genusMiliusa and widely distributed inM. balansae stem,M. cuneatastem and leaf,M. mollistwig,M. sinensis leaf and branch, andM. velutinastem bark [21, 23–26, 37]. With the exception of new compounds and two known others,12 and28, it was remarked that the remaining compounds were isolated from this genus for the first time.Miliusa alkaloids can be found in formulating a variety of main skeletons, such as aporphine and oxo-aporphine backbones in respective asimilobine (1) and 10-hydroxyliriodenine (7), tetrahydroisoquinoline and quinolone in respective coclaurine (2) and N-methylcorydaldine (16), azafluorenone in kinabaline (10), dihydroprotoberberine and oxo-protoberberine in respective 2,10-dimethoxy-3,11-dihydroxy-5,6-dihydroprotoberberine (5) and miliusacunine A (18), benzylisoquinoline in reticuline (30), or morphinan in salutarine (31).Taking the newly isolated alkaloids into consideration, two new oxo-aporphine and dihydroprotoberberine alkaloids4-5, in addition to thirteen known others (Table 1), were obtained from 95% ethanol extract of air-dried and powdered stem and leaf ofM. cuneata [21]. One of the immensely value aspects of 2,10-dimethoxy-3,11-dihydroxy-5,6-dihydroprotoberberine (5) is that this compound possessed the positive and negative charges in nitrogen and oxygen atoms, respectively [21]. Khan and Kumar (2015) suggested that alkaloids with bipolar charges had a tendency to bind to the serum proteins better than that of neutral compounds [43].Following the outcomes in the isolation and NMR-structural elucidation, 10-methoxyliriodenine (14) was a known alkaloid, but its 10-hydroxylated derivative7 was determined to be a new oxo-aporphine alkaloid in nature; both of these two compounds were precipitated out of the MeCOEt extract (2.8 g) ofM. CF.banacea species [4]. Likewise, isocorydine (8), especially its new unusual derivative (+)-isocorydine α-N-oxide (9), has successfully been separated from extracts ofM. velutina stem bark [22, 23].An additional significance in phytochemical works related to plants is that the leaf ofM. cuneata species is likely to be a rich source of oxo-protoberberine alkaloids. In 2005, five new alkaloids of type oxo-protoberberine were isolated from the acetone extract ofM. cuneataleaf, trivially named miliusacunines A-E (18-22) [7].Finally, three alkaloids, consisting of two new dihydro-oxo-protoberberine derivatives miliusathorines A-B (23-24) and known one (−)-norushinsunine (28), have been purified from the combined extract between stem and root ofM. thorelii species [8].


## 3.2. Geranylated Homogentisic Acid Derivatives

Phenolic acids of type homogentisic acids are usually detected in both terrestrial plants and bacterial pathogenic strains [44, 45]. Homogentisic acids indicated the significant antioxidant and anti-inflammatory capacities, but the excess accumulation of these can cause “alkapton” symptom in the human body [45, 46].Considerable attention should be paid to the novel class of geranylated homogentisic acid derivatives from plants of genusMiliusa. Among the total forty-one isolated compounds33-73, secondary metabolites40-73 were novel and relatively rare compounds in nature while a number of isolates35-39 were new in literature.General features were highlighted in the chemical structures33-34 and36-72; that is, carbonylation and geranylation often occurred at carbons C-2 (or C-2′) and C-1 (or C-1′), respectively (Figure 2). Furthermore, double bonds might be located at carbons C-3 and C-4 (or C-3′ and C-4′); hydroxylation, methoxylation, or acetoxylation was normally observed at carbon C-5 (or C-5′).Of isolated compounds40-72, most of these unique structures might possibly be formed by a rare C-18 skeleton, containing a characteristic γ-lactone spiro-ring system. Five-member γ-lactone ring were geranylated in the structures40-57,61-67, and72, but were found to be opened in the structures58-60 and68-71. Two isolated compounds59-60 also contained a tetrahydrofuran ring. Additionally, the combination of NOE effect observations, Mosher reactions, and X-ray measurements allowed for determining the absolute configuration, in which 1R,5S,1′R-form and 5β-orientation were suitable for the group of compounds40-72 [14]. C13-NMR provided the evidence of chemical shifts δC, thereby showing that, at carbons C-1, C-5, and C-1′ of compounds containing spiro-ring system, δC reachedca. 52.0-56.0 ppm,ca. 63.0-68.0 ppm, andca. 26 ppm, respectively.As part of an interdependent work, more recently, Promgool et al. (2019) reported that chromatographic separation of extracts ofM. velutinafruit and flower has resulted in isolating and elucidating five new rare geranylated homogentisic acid derivatives, miliusanal (35) and miliusanones A-D (36-39), in addition to known ones, methyl 2-(1′β-geranyl-5′β-hydroxy-2′-oxocyclohex-3′-enyl) acetate (33) and 2-(1′β-geranyl-5′β-hydroxy-2′-oxocyclohex-3′-enyl) acetic acid (34) [32]. New compound35 indicated the property of a phenolic aldehyde with CHO (δC 196.1 ppm in solvent CDCl3), whereas new compounds38-39 were significantly made of 6′′-hydroxylated groups (δC 75.6-77.4 ppm in solvent CDCl3 + CD3OD).Novel (+)-miliusate (40) was one of the interesting constituents of Vietnamese plantM. balansae [31]. After that, it was reported appearing in two other species:M. sinensisleaf, twig and flower, andM. umpangensis leaf [14, 19, 33, 34]. So far, the methanol-water extract (95:5, v/v) of Vietnamese plantM. balansae leaf and branch has shown to comprise one novel compound, (+)-miliusol (72), and one new natural product, miliusolide (73) [30]. In NOE interactions H-3a to H-5 and H-7a were key evidence to determine these three protons with orientedcis-shape and the absolute configuration was established as 3aS,5S,7aRin compound73.Novel geranylated homogentisic acids derivedMiliusa plants were more commonly referred to by their trivial name. By using Table 1 and Figure 2, we continue to make comments relating to a serial number of (+)-miliusanes I-XXXI (41-71). Secondary metabolites41-60 were separated from dichloromethane extract of the other Vietnamese plantM. sinensisleaf, twig, and flower, whereas the remaining members61-71, once again, derived fromM. balansae species [13, 14]. As shown in Figure 2, the plausible biogenetic pathway explained why these compounds were classified as geranylated homogentisic acids, in which the first step involved the combination between precursor homogentisic acid and geranyl unit of geranyl diphosphate (geranyl PP). Obviously, the methylation of intermediate productA produced compound53 while lactone ring-cyclization and dehydrate applied toA would give72; compound53 was then joined to epoxide ring-cyclization reaction and dehydrated to form59 [14].Taken together, serial compounds40-72 were useful biomarkers for either genusMiliusa or family Annonaceae, and they also accounted for the close relationship between the two speciesM. balansaeandM. sinensis.


## 3.3. Flavonoids

Now we do take a point of crucial information in mentioning another class ofMiliusa metabolites. Phytochemical investigations onMiliusa species also proved the existence of flavonoids. Flavonoids were detected in leaf, twig, branch, stem, or root of nine plants:M. balansae,M. cuneata,M. fragrans,M. mollis,M. sinensis,M. smithiae,M. thorelii,M. umpangensis, andM. velutina, to date (Table 2). Herein, we draw a list of forty-three isolated compounds74-116 fromMiliusa species. Chemical index also exhibited thatMiliusaflavonoids can be divided into several main groups: flavonols74-105, chalcones106-109, flavanones110-115, and flavan116 (Table 1 and Figure 3) [7, 8, 11, 25, 30, 33, 35–37]. More than thirty flavonols were found but flavones and isoflavones were absent, to the best of our knowledge. Likewise, flavanones and isoflavanones have not been recorded yet.The most important information to be gained from structural features is that isolated flavonoids derived fromMiliusa species were generated asmono-flavonoid derivatives. The phenomenon of methoxylation occurred at carbon C-3 of most isolated flavonols. Normally, flavonols and flavanones were associated with substituents at carbons C-5, C-6, C-7, C-8, C-3', and C-4' by hydroxy and methoxyl groups.Despite the fact that the known flavonoids74,77-82,84-91,96-99,101-103,105-107,109, and114-115 are abundant in the plant kingdom, these compounds were reported fromMiliusa species for the first time. Rutin (104) was recognized to be only flavonol glycoside isolated from plants of genusMiliusa. In the meantime, (−)-epicatechin (116) was also a unique flavan to be found.M. thorelii species seemed to be a rich supply of flavonols. Bioguided assay and fractionation of extracts of leaf, stem, and root afforded one new natural product, miliusathorone (92), in addition to nineteen known ones,74,80-83,85-86,88-91, and95-102 [8]. New metabolite92 had the characteristic remark with chemical shifts of -O-CH2-O- [δH 6.06, δC 101.8]. Interestingly, new metabolite named miliufavol (92) was derived from methanol-water (95:5, v/v) extract of air-dried groundM. balansae leaf and branch [35], in which this compound was an uncommon flavonol by combining of pachypodol (95) and benzyl unit at carbon C-8.Four chalcone derivatives, 2′,6′-dihydroxy-4′-methoxydihydrochalcone (106), 4′,6′-dihydroxy-2′,3′,4-trimethoxydihydrochalcone (107), dihydropashanone (108), and pashanone (109), were significant constituents of the two Vietnamese plantsM. balansaeandM. sinensis [25, 31, 37]. In contrast to109, three compounds106-108 belong to dihydrochalcone, and compound107 was a new isolated compound in literature. Isolated flavanones110-113 were also considered as main components of VietnameseM. balansaeandM. sinensis, but two compounds, final derivatives 7-O-methyleriodictyol (114) and sakuranetin (115), were only detected inM. velutinaleaf up to now [38].


## 3.4. Lignans and Neolignans

We continuously provide the next phytochemical profiles of the other class of isolated compounds. Starting with the deepest aim to find biologically active molecules from genusMiliusa, four lignans117-120 and twenty-four neolignans121-144 have also been isolated (Table 1 and Figure 4). In addition, these phytochemicals from genusMiliusa originated from three parts, leaf, stem, and twig, of two main species,M. fragrans andM. mollis, but occasionally found inM. cuneataspecies [8–10, 24].It is possible to set up a clear arrangement for backbones of either lignans or neolignans.Miliusa lignans were able to form up to two main skeletons, tetrahydrofuran lignan (compounds117-118 and120) and 7,9′:7′,9-diepoxylignan (compound119). In the case of neolignans, three main scaffolds can be found, namely, 8.O.4′-neolignan (compounds121,132,137-138, and142-144), 7.O.3′,8.O.4′-neolignan (124-125,128-130,135, and139), and dihydrobenzofuran skeleton (compounds122-123,126-127,131,133-134,136, and140-141). Two skeletons of 8.O.4′-neolignan and 7.O.3′,8.O.4′-neolignan were only represented in the two Thai speciesM. fragrans andM. mollis, thereby suggesting the close relationship between them [9, 10, 24].Besides geranylated homogentisic acids, oxo-protoberberine alkaloids, and flavonols, chemical constituents ofM. cuneataleaf were also in association with the presence of the well-known lignan (+)-syringaresinol (119) [7]. In 2013, sixteen secondary metabolites, being isolated from methanol extracts of ThaiM. fragransleaf and stem in the work of Sawasdee and partners, were described as three lignans117-118,120 and thirteen neolignans121,124-125,128-131,135,137-139, and143-144 [9]. The new lignan (+)-3-hydroxyveraguensin (117) and its relatives118 and120 have been structurally established as 7S,8S,7′R,8′S-configuration (cis-H-7/H-7′,cis-H-7′/H-8′,trans-H-7/H-8, andtrans-H-8/H-8′). The new neolignans124-125,128,135, and139 and two known ones129-130 shared the same structure of three parts, 5-methoxyl-phenylpropanoid unit, 2-methyl-1,4-dioxane unit, and phenyl ring linkage to carbon C-7. However, the absolute configurations were elucidated as 7S,8R for124-125 and129-130, 7S,8Sfor128, and 7R,8Rfor135 and139, but the stereochemistry for new 8.O.4′-neolignans137-138 and their analogs138 and144 could not be determined.In the two years 2010 and 2013, Sawadee and partners provided the results of the phytochemical isolation and NMR-structural elucidation of ThaiM. mollis, in which one new neolignan of type dihydrobenzofuran (2S,3S)-2,3-dihydro-2-(4-methoxyphenyl)-3-methyl-5-[1(E)-propenyl]benzofuran (127), one new 8.O.4′-neolignan (7S,8S)-threo-Δ8′-4-methoxyneolignan (132), and two known others123 and126 were isolated from twig; five new neolignans of type dihydrobenzofuran 7-methoxymiliumollin (133), 3′-methoxymiliumollin (134), 4′-O-methylmiliumollin (136), miliumollin (140), miliumollinone (141); one new 8.O.4′-neolignan miliusanollin (142); and one known other (123) were derived from leaf [9, 10].Neolignans of type dihydrobenzofuran from Thai plants have been shown to be associated with 2R,3R-absolute configuration (trans-H-2/H-3) in groups122-123,126,133-134, and140-141 and 2S,3S-absolute configuration (cis-H-2/H-3) in127 and136, while new compound132 set up 7S,8S-model when compared to 7R,8R-model in142 and 7S,8R-model in143.


## 3.5. Acetogenins and Lactones

A bit of the attractive phytochemical outcome arose from the class of isolated acetogenins. As we know, acetogenins and their analogs are now remarkable characteristics of the family Annonaceae [47]. From Table 1 and Figure 5, isolated acetogenins existed in bark, stem bark, flower, and leaf ofM. velutina species and they were new compounds except for goniothalamusin (158). The most striking feature is that these isolated compounds were able to form up to one or two triple bonds in a long aliphatic side chain terminated by γ-hydroxy (or γ-methoxyl)-γ-lactone unit, methyl group, or double bond.Earlier phytochemical report by Jumana and coauthors (2000) showed that acetogenins A-B (145-146) obtained from BangladeshisM. velutina species reached up to 0.00154% and 0.008% of extract weight, respectively [5]. However, NMR data of long alkyl side chain of these two compounds remain unknown. Paying attention to the result of phytochemical study onn-hexane extract of ThaiM. velutinastem bark, based on repeating chromatographic columns on silica gel and sequential LiChrosorb RP-18 column techniques, we found that eight new compounds, alphabetically named cananginones A-I (147-155), have been successfully isolated as colorless viscous liquids [40]. Taking cananginone A (147) as an example, this new C23 linear olefinic acetogenin is accompanied by a variety of significant chemical shifts [(γ-methoxyl)-γ-lactone] unit established at δC 179.6 (C-1), δC 39.2 (C-2), δC 30.4 (C-21), δC 76.7 (C-22), δC 74.3 (C-23), and δC 59.5 (C-24); two double bonds and two triple bonds occurring at δC 65.1-146.6 ppm] [40]. Additionally, the positive OR value of +17.4 (c 0.206, CHCl3) evidently confirmed 2R,22S-configuration compared with that of goniothalamusin (158) [+14.6 (c 0.206, CHCl3)] [40].Miliusolide and its dihydro derivatives156-157 were also new derivatives of acetogenin detected inM. velutina stem bark [39]. Unfortunately, the trivial name ‘miliusolide’ was used for both metabolites73 and156 [30, 39].In the light of phytochemical research, Wongsa and partners (2017) continuously provided the outcome relative to ThaiM. velutina species (Figure 5) [38]. Fromn-hexane and ethyl acetate extracts of leaf of this plant, a rare class of eight bicyclic lactones with a C18 carbon backbone, trivially named velutinones A-H (161-168), were isolated. Similar to acetogenins, these compounds were collected with the physical property of colorless viscous liquids. Furthermore, they had shown the same feature in chemical structures, by which geranyl groups are located at carbon C-2a and the relative configuration at carbons C-2a and C-6a wassyn-model (2aR,6aR). In general, it is worth concluding that olefinic acetogenins with terminated γ-lactone and 2-geranylated bicyclic lactones indicated a great crucial role in chemotaxonomic aspect to recognizeM. velutina. Lactones in genusMiliusawere also found inM. balansae; the two known compounds curcolide (159) and serralactone (160) were two components of the leaf of this plant, collected from Vietnam [11].


## 3.6. Styryls

Most of secondary metabolites of interest to chemists pointed out that styryl derivatives were found in genusMiliusa. Styryls presented as the significant constituents of the two speciesM. balansae andM. velutina [31, 32, 38, 41]. As shown in Table 1 and Figure 6, the threemono-styryls169-171 and the fivebis-styryls172-176 have been updated. It is worth noting that yangonin (171) was, for the first time, reported from genusMiliusa, while the seven remaining isolates169 and172-176 were reported to be new compounds in nature.The shrub treeM. balansaeis widely distributed in Vietnam and China; chromatographic examination of the polar extract of leaf and branch of this plant yielded the two new mono-styryls 3,4-dimethoxy-6-styryl-pyran-2-one (169) and (2E,5E)-2-methoxy-4-oxo-6-phenyl-hexa-2,5-dienoic acid methyl ester (170) [31].Regarding isolated compounds of typebis-styryls, the general chemical structure was designated by cyclobutyl nucleus, while side chains were made up of phenyl rings, α-pyrone rings, and α,β-unsaturated ketones.In order to identify bioactive constituents, phytochemical investigation has been carried out on methanol-water extract (95:5, v/v) of VietnameseM. balansae leaf and branch, which continuously demonstrated the existence of two bulk newbis-styryls miliubisstyryls A-B (172-173). Although NMR data of172 were not completely assigned, the key NOE evidence proposed that the relative configurations of172 and173 were identical, beingtrans-form for H-7/H-8 and H-7′/H-8′, together withcis-form for H-8/H-7′ and H-7/H-8′.As mentioned above,M. velutinais a good reservoir of unique bicyclic lactones. From this plant, the three newbis-styryls velutinindimers A-C (174-176) were also separated [38]. According to this article, OR value approximately reached zero ([α]D +0.08 (c 0.63, MeOH-CHCl3 3:1)] and no Cotton effect was observed in CD spectrum which can be responsible for the symmetrical property of velutinindimer A (174) (compound containing a symmetrical plane). Similarly, the combination of the assignments of 1H, 13C-NMR spectroscopic signals and the correlations in 2D-NMR data, as well as the most utilization of advantageous techniques such as the CD and X-ray measurements that considered velutinindimers B-C (175-176), were two racemic compounds and the relative configurations of these compounds were 5′S,6′R,7S,8S in compound175 ([α]D +0.08 (c 0.63, MeOH-CHCl3 5:1)) and 5′R,6′S,7R,8S in compound176 ([α]D +0.03 (c 0.23, MeOH-CHCl3 9:1)).


## 3.7. Terpenoids and Phenols

M. balansae species seems to be the most crucial objective in the contents of phytochemical researches related to plants ofMiliusa species. Following the application of the variously chromatographic methods, norsesquiterpenoids of type megastigmanes,mono-phenols, and their glycosides have been determined as characteristics of genusMiliusa, especiallyM. balansae species. Eight terpenoids177-185 and thirteen phenolic compounds186-198 were summarized in Table 1 and Figure 7, which were newly isolated compounds or isolated for the first time from genusMiliusa [11, 25, 30, 32, 37, 42].Herein, mono-saccharide units of typeβ-D-glucopyranosyl parts and disaccharides units of type α-D-apiofuranosyl-(1→6)-O-β-D-glucopyranosyl, β-D-apiofuranosyl-(1→6)-O-β-D-glucopyranosyl, β-xylopyranosyl-(1→6)-O-β-D-glucopyranoside, α-L-rhamnosyl-(1→6)-β-D-glucopyranosyl moieties are glycone parts linked to aglycones of terpenoids and phenols, whereas aglycones of phenols are mostly structurally formed by phenylethanoid nucleus.Together with the one known terpenoid alangionoside B (177) and the four known phenolic glycosides cuchiloside (187), osmanthuside H (195), 1-(α-L-rhamnosyl-(1→6)-β-D-glucopyranosyloxy)-3,4,5-trimethoxybenzene (196), and 3,4,5-trimethoxyphenol-β-D-glucopyranoside (197), the phytochemical investigation of ChineseM. balansae species afforded one new megastigmane glycoside miliusoside C (182) and two newmono-phenols of type phenylethanoid glycosides miliusosides A-B (193-194) from 80% ethanol extract of dried stem [42]. The newly isolated compound182 differed from its similar structure177 in the orientation of D-apiosyl unit (α-form in182 and β-form in177).In VietnameseM. sinensisleaf and branch, 24-methylencycloartane-3β,21-diol (185) was the only triterpenoid reported to date, whereas the small-simple molecules 4-hydroxybenzonitrile (188), 4-hydroxybenzaldehyde (189), and isovanillin (191) weremono-phenols fromM. velutinafruit [25, 32, 37].Phytochemical analysis of methanol extract of VietnameseM. balansae leaf has permitted the isolation and determination of the three new megastigmane glycosides milbasides A-C (179-181), in addition to the three analogs ampelopsisionoside (178), myrsinionosides A and D (183-184), and one glucosylated phenol 1-(3-methylbutyryl)phloroglucinol-glucopyranoside (192) [11]. Structures179-181 shared the sameE-geometrical shape of double bond outside; in addition, due to the negative Cotton effect at around 240 nm (Δε ranged from –1.73 to –3.27), the absolute configurations of179-180 were 2R,3S,5S,6S, while compound181 was proposed as 3S,5R,6R(Δε245nm +3.27). In the same manner, chemical shift of methylene group ofbis(2-hydroxyphenyl) methyl ether (186) was higher than that of hydroxymethyl alcohol by 8 ppm, implying that compound186 was a new symmetrical ether [30].This review updated a phytochemical result ofM. mollis; the twig of this plant also contained the two phenolic glycosides icariside D2 (190) and tyrosol 1-O-β-xylopyranosyl-(1→6)-O-β-D-glucopyranoside (198) [24]. The highlight in phenyl ring of aglycone of new compound198 corresponded to A2B2 spin system [δH 7.10 (2H, d,J = 8.6 Hz, H-3 and H-5) and δH 6.95 (2H, d,J = 8.6 Hz, H-2 and H-6)], with glycone being remarked with two anomeric protons at δH 4.73 (1H, d,J = 7.3 Hz, H-1′) and δH 4.17 (1H, d,J= 7.6 Hz, H-1′′).


## 3.8. Amine, Amide, Alcohol Derivatives and Miscellaneous Types

A phytochemical survey conducted by Yu and partners (2009) pointed out thatM. balansae leaf, collected from China, has also been composed of one amine adenine riboside (199), and two amide allantoin (200), and uridine (204) (Figure 8) [26]. Although these compounds are now available in the natural plants, they were isolated as single compounds from genusMiliusa for the first time. Utilizing silica gel (63-200 μm) and sephadex LH-20 columns in the chromatographic isolation, three tyramine derivatives,N-trans-caffeoyltyramine (201),N-trans-coumaroyltyramine (202), andN-trans-feruloyltyramine (203), have been purified from acetone ofM.cuneata air-dried twig [7]. Since then, acetone extract ofM. thorelii stem and root was demonstrated to contain two isolates,201 and203 too [8].VietnameseM. balansae species might have been considered as a rich resource of diverse compounds. Based on the evidence of phytochemical findings and NMR explanations, six well-known alcohol derivatives,205-210, were further obtained from the leaf of this plant for the first time [11]. Among them, β-D-glucopyranoside (Z)-3-hexenol (205) was a glycosylation of longn-alkyl side chain alcohol, while the five remaining ones206-210 were categorized as two pairs oferythro andthreo isomers of glycerols and one other glucosylated glycerol. They wereerythro-guaiacylglycerol (206),threo-guaiacylglycerol (207),erythro-1-C-syringylglycerol (209),threo-1-C-syringylglycerol (210), and (L)-guaiacyl glycerol 2′-O-β-D-glucopyranoside (208), respectively. There were also records of these compounds from genusMiliusa for the first time.As can be seen, the difference of chemical components from Vietnamese and Chinese M.balansae species has been depending on geographic factor more often.Besides the presence of the rare compounds of type homogentisic acid derivatives, the ethyl acetate extract of air-driedM. velutina fruit also consisted of furfural derivatives, in which three small molecules, 5-acetyloxymethylfurfural (211), 5-hydroxymethylfurfural (212), and 5-methoxyfurfural (213), were isolated [32]. Despite the fact that these compounds were formulated with a simple pattern, they were recorded from the plants of genusMiliusa for the first time.As shown in Figure9 and Table 1, the common chemical compounds of type phytosterols can be found in severalMiliusa plants. For instance,M. balansaestem was reported to contain β-sitosterol (216), and its glucoside(217), or stigmasterol (219); this one turned out to be one of the components from bothM. sinensisleaf and branch andM. velutina fruit and flower [25, 32].Chromatographic separation of the extracts fromM. balansaestem also led to the isolation and determination of two mono-saccharide D-glucose (214) and sucrose (220) whereasM. balansaeleaf and branch were accompanied by the existence of fatty acid octacosanoic acid (215) and benzoate sodium (218) [26, 32, 41].


## 3.9. Essential Oils

For a long time, there have been researches related to essential oils, which have frequently played an important role and been regarded as a branch of either phytochemistry or pharmacological products findings [1]. Many studies focused on the applications providing multifunction in healthcare problems, alternative medicines, food and drink manufacturers, or household cleaning products. Normally, the distillation method, often by using water steam, is a prompt and efficacious way; in addition, the extractions of solvent or florasols have always been used depending on the raw materials. The systematic GC and GC-MS techniques are usually being used to identify volatile individuals.Miliusa species are also among the largest sources of this specific chemical compound. In the review of all circumstances, following the results of ethno-geographic distribution, species property, part use, extraction method, and GC-MS technical analysis, the results of studying essential oils ofMiliusa species were compiled in Table 2.Essential oils studies onMiliusaplants are quite limited. There have been only three reports to date. Among forty-six members identified from essential oils of fresh leaf of, Quang Binh, VietnameseM. baillonii species, the main constituentZ-citral reached the highest amount of 41.2% [28].M. sinensis species, collected from Nghe An, Vietnam, is also likely to be a rich resource of essential oils. From this plant, 67.1% of a total of 95.1% of essential oils were sesquiterpene hydrocarbons [29]. Significantly, α-humulene and β-caryophyllene could be seen as the main components of oils of these two VietnameseMiliusa plants (Table 2). In the same manner, the properties of plants, environmental factors, and collection time accounted for the differential components in essential oils of three, Queensland, AustralianMiliusaplants,M. brahei,M. horsfieldii, andM. traceyi [27]. As can be seen from Table 2, these three species yielded oils, in which terpenoids predominated. α-Humulene, β-caryophyllene, and bicyclogermacrene achieved more than 10% of oils ofM. brahei, while the major sesquiterpene of type caryophyllene derivatives ranged from 12% to 20%, present inM. horsfieldii oils; the highest components in oils of last plantM. traceyi encountered were the two isomers α- and β-pinene (approximately 19%). Of particular interest, β-caryophyllene was found to be one of the main compounds in all the five species (Table 2), which accounted for 10% to 20% of oils ofMiliusa species.


## 4. Pharmacological Activities

### 4.1. Cytotoxic Activity

The plants of genusMiliusa included sets of variously useful isolated components to the 得 experimentally cytotoxic targets. In the review of all conditions, the cytotoxic results were briefly summarized in Table 3. Earlier report in 2000 by Jumana and partners mentioned the cytotoxicity of constituents fromM. velutina species; the LC90 results of tested compounds may run as acetogenin A (145) (LC90 7.1 μg/mL) > acetogenin B (146) (LC90 14.1 μg/mL) > positive control vincristine (LC90 15.0 μg/mL) > goniothalamusin (158) (LC90 20.0 μg/mL) [5]. Nine new acetogenins cananginones A-I (147-155) were found to possess the weak IC50 values of 16.6-129.7 μM or be inactive in the cytotoxic assay against three cancer cell lines KB, MCF7, and NCI-H187, when compared to those of reference compound doxorubicin (IC50 0.46-1.05 μM) [40].Table 3
Cytotoxic results ofMiliusa components.
No Inhibitory concentrations (cell lines) References Isolated compound  12 IC50 2.89 μg/mL (MCF-7), IC50 6.66 μg/mL (LU), IC50 5.23 μg/mL (Hep-G2) and IC50 2.30 μg/mL (KB) [37]  18-22 Inactive (KB and Vero) [7]  33 IC50 26.5 μg/mL (KB), IC50 32.7 μg/mL (MCF-7), IC50 5.8 μg/mL (NCI-H187) and IC50 6.3 μg/mL (Vero) [32]  34 IC50 11.8 μg/mL (KB), IC50 > 50.0 μg/mL (MCF-7), IC50 6.1 μg/mL (NCI-H187) and IC50 17.7 μg/mL (Vero) [32]  35 IC50 9.3 μg/mL (KB), IC50 3.6 μg/mL (MCF-7), IC50 40.4 μg/mL (NCI-H187) and IC50 39.1 μg/mL (Vero) [32]  36 IC50 11.9 μg/mL (KB), IC50 23.2 μg/mL (MCF-7), IC50 6.1 μg/mL (NCI-H187) and IC50 16.1 μg/mL (Vero) [32]  37 IC50 17.9 μg/mL (KB), IC50 26.4 μg/mL (MCF-7), IC50 6.2 μg/mL (NCI-H187) and IC50 5.8 μg/mL (Vero) [32]  38 IC50 > 50.0 μg/mL (KB, MCF-7, NCI-H187, Vero) [32]  39 IC50 > 50.0 μg/mL (KB, MCF-7, NCI-H187, Vero) [32]  40 IC50 1.18 μg/mL (KB), IC50 2.02 μg/mL (Lu1), IC50 1.56 μg/mL (Col2), IC50 3.18 μg/mL (LNCaP), IC50 3.58 μg/mL (MCF-7), IC50 2.89 μg/mL (HUVEC), IC50 0.32 μg/mL (HL60), IC50 2.70 ± 0.09 μM (HCT116), IC50 1.67 ± 0.11 μM (A375) and IC50 6.97 ± 0.16 μM (A549) [13, 14]  41 IC50 1.40 μg/mL (KB), IC50 2.86 μg/mL (Lu1), IC50 2.92 μg/mL (Col2), IC50 5.06 μg/mL (LNCaP), IC50 2.23 μg/mL (MCF-7), IC50 1.79 μg/mL (HUVEC), IC50 0.45 μg/mL (HL60), IC50 3.50 ± 0.02 μM (HCT116), IC50 3.70 ± 0.11 μM (A375) and IC50 4.36 ± 0.40 μM (A549) [13, 14]  42 IC50 5.45 μg/mL (KB), IC50 5.80 μg/mL (Lu1), IC50 9.40 μg/mL (Col2), IC50 19.64 μg/mL (LNCaP), IC50 21.34 μg/mL (MCF-7), IC50 6.55 μg/mL (HUVEC), IC50 1.73 μg/mL (HL60), IC50 17.2 ± 1.86 μM (HCT116), IC50 9.86 ± 0.19 μM (A375) and IC50 18.4 ± 0.35 μM (A549) [13, 14]  43 IC50 1.18 μg/mL (KB), IC50 4.84 μg/mL (Lu1), IC50 4.29 μg/mL (Col2), IC50 5.06 μg/mL (LNCaP), IC50 2.61 μg/mL (MCF-7) and IC50 0.56 μg/mL (HL60) [14]  44 IC50 32.17 μg/mL (KB), IC50 60.43 μg/mL (Lu1), IC50 38.45 μg/mL (Col2), IC50 > 62.0 μg/mL (LNCaP), IC50 15.78 μg/mL (MCF-7) and IC50 18.66 μg/mL (HL60) [14]  45 IC50 > 55.0 μg/mL (KB, Lu1, Col2, LNCaP and MCF-7) and IC50 52.29 μg/mL (HL60) [14]  46 IC50 3.97 μg/mL (KB), IC50 6.61 μg/mL (Lu1), IC50 4.23 μg/mL (Col2), IC50 5.29 μg/mL (LNCaP) and IC50 4.76 μg/mL (MCF-7) [14]  47 IC50 5.82 μg/mL (KB), IC50 6.16 μg/mL (Lu1), IC50 3.70 μg/mL (Col2), IC50 5.82 μg/mL (LNCaP) and IC50 6.08 μg/mL (MCF-7) [14]  48 IC50 47.35 μg/mL (KB), IC50 63.58 μg/mL (Lu1), IC50 33.44 μg/mL (Col2), IC50 43.38 μg/mL (LNCaP), IC50 26.42 μg/mL (MCF-7) and IC50 > 10.9 μg/mL (HUVEC) [14]  49 IC50 > 57.4 μg/mL (KB, Lu1, LNCaP), IC50 46.01 μg/mL (Col2), IC50 52.56 μg/mL (MCF-7), IC50 13.3 ± 0.62 μM (HCT116), IC50 7.24 ± 0.81 μM (A375) and IC50 18.3 ± 2.54 μM (A549) [13, 14]  50/51 IC50 5.22 μg/mL (KB), IC50 21.44 μg/mL (Lu1), IC50 8.03 μg/mL (Col2), IC50 29.56 μg/mL (LNCaP), IC50 5.03 μg/mL (MCF-7) and IC50 3.28 μg/mL (HL60) [14]  52/53 IC50 54.97 μg/mL (KB), IC50 9.31 μg/mL (Lu1), IC50 13.43 μg/mL (Col2), IC50 51.82 μg/mL (LNCaP) and IC50 12.18 μg/mL (MCF-7) [14]  54/55 IC50 5.28 μg/mL (KB), IC50 7.46 μg/mL (Lu1), IC50 5.36 μg/mL (Col2), IC50 27.62 μg/mL (LNCaP), IC50 10.06 μg/mL (MCF-7), IC50 3.30 ± 0.06 μM (HCT116), IC50 3.38 ± 0.09 μM (A375) and IC50 10.4 ± 0.32 μM (A549) [13, 14]  56 IC50 6.11 μg/mL (KB), IC50 19.94 μg/mL (Lu1), IC50 3.89 μg/mL (Col2), IC50 6.11 μg/mL (LNCaP) and IC50 6.39 μg/mL (MCF-7) [14]  57 IC50 6.71 μg/mL (KB), IC50 14.94 μg/mL (Lu1), IC50 9.48 μg/mL (Col2), IC50 23.95 μg/mL (LNCaP), IC50 10.99 μg/mL (MCF-7), IC50 4.20 ± 0.30 μM (HCT116), IC50 4.25 ± 0.05 μM (A375) and IC50 20.8 ± 1.24 μM (A549) [13, 14]  58 IC50 3.07 μg/mL (KB), IC50 1.82 μg/mL (Lu1), IC50 2.26 μg/mL (Col2), IC50 2.41 μg/mL (LNCaP), IC50 3.01 μg/mL (MCF-7) and IC50 0.63 μg/mL (HL60) [14]  59 IC50 2.61 μg/mL (KB), IC50 1.82 μg/mL (Lu1), IC50 2.01 μg/mL (Col2), IC50 1.73 μg/mL (LNCaP) and IC50 2.26 μg/mL (MCF-7) [14]  60 IC50 > 59.0 μg/mL (KB, Lu1, Col2, LNCaP and MCF-7) and IC50 57.01 μg/mL (HL60) [14]  61 IC50 > 65.0 μg/mL (HCT116, A375, A549) [13]  62/63 IC50 9.80 ± 0.51 μM (HCT116), IC50 6.96 ± 0.23 μM (A375) and IC50 24.3 ± 1.42 μM (A549) [13]  64/65 IC50 > 52.9 μM (HCT116, A375 and A549) [13]  66/67 IC50 > 55.0 μM (HCT116, A375 and A549) [13]  68 IC50 4.10 ± 0.13 μM (HCT116), IC50 3.60 ± 0.33 μM (A375) and IC50 7.15 ± 0.18 μM (A549) [13]  69 IC50 > 57.5 μM (HCT116, A375 and A549) [13]  70 IC50 13.0 ± 0.17 μM (HCT116), IC50 10.4 ± 0.66 μM (A375) and IC50 24.5 ± 1.56 μM (A549) [13]  71 IC50 18.3 ± 0.59 μM (HCT116), IC50 11.6 ± 1.45 μM (A375) and IC50 18.0 ± 2.80 μM (A549) [13]  72 IC50 10.2 ± 0.1 μM (KB)b, IC50 13.5 ± 0.5 μM (Vero), IC50 2.00 ± 0.16 μM (HCT116), IC50 1.50 ± 0.15 μM (A375), IC50 2.45 ± 0.24 μM (A549), IC50 1.18 μg/mL (KB)c, IC50 1.64 μg/mL (Lu1), IC50 1.35 μg/mL (Col2), IC50 1.78 μg/mL (LNCaP), IC50 3.09 μg/mL (MCF-7), IC50 1.32 μg/mL (HUVEC) and IC50 0.66 μg/mL (HL60) [7]b; [13], [14]c  75 ED50 3.6 μg/mL (P-388), ED50 0.76 μg/mL (Col2), ED50 0.68 μg/mL (MCF-7)ED50 16.08 μg/mL (ASK), ED50 2.81 μg/mL (Hek293) and Inactive (KB, Lu-1 and T24) [36]  76 IC50 4.6 μg/mL (KB), IC50 0.93 μg/mL (Hep-G2) and IC50 > 5.0 μg/mL (RD) [35]  77 IC50 4.3 μg/mL (KB), IC50 0.57 μg/mL (Hep-G2) and IC50 2.09 μg/mL (RD) [35]  79 and 107 IC50 > 128.0 μg/mL (MCF-7, LU, Hep-G2 and KB) [37]  83 and 87 Inactive (KB and Vero) [7]  94 > 5.0μg/mL (KB and RD) and 1.5 μg/mL (Hep-G2) [35]  95 IC50 0.7 μg/mL (KB), IC50 0.55 μg/mL (Hep-G2) and IC50 3.01 μg/mL (RD) [35]  116 Inactive (KB, MCF-7 and NCI-H187) [9]  119 Inactive (KB and Vero) [7]  123 IC50 137.4 μM (KB), IC50 169.1 μM (MCF-7) and IC50 94.7 μM (NCI-H178) [10]  124 IC50 20.0 μg/mL (KB), IC50 21.0 μg/mL (MCF-7) and IC50 17.1 μg/mL (NCI-H178) [9]  125 IC50 17.9 μg/mL (KB), IC50 28.4 μg/mL (MCF-7) and IC50 15.9 μg/mL (NCI-H178) [9]  130 IC50 18.4 μg/mL (KB), IC50 22.6 μg/mL (MCF-7) and IC50 20.6 μg/mL (NCI-H178) [9]  131 IC50 12.9 μg/mL (KB), IC50 45.6 μg/mL (MCF-7) and IC50 16.7 μg/mL (NCI-H178) [9]  134 IC50 31.4 μM (KB), IC50 56.2 μM (MCF-7) and IC50 61.3 μM (NCI-H178) [10]  139 IC50 23.8 μg/mL (KB), IC50 24.4 μg/mL (MCF-7) and IC50 16.7 μg/mL (NCI-H178) [9]  140 IC50 27.2 μM (KB), IC50 71.9 μM (MCF-7) and IC50 95.3 μM (NCI-H178) [10]  141 IC50 95.9 μM (KB), IC50 142.7 μM (MCF-7) and IC50 115.9 μM (NCI-H178) [10]  143 IC50 14.4 μg/mL (KB), IC50 13.0 μg/mL (MCF-7) and IC50 12.7 μg/mL (NCI-H178) [9]  145 LD90 7.1 μg/mL [5]  146 LD90 14.1 μg/mL [5]  147 IC50 99.0 μM (KB), Inactive (MCF7) and IC50 48.9 μM (NCI-H187) [40]  148 IC50 67.4 μM (KB), IC50 93.7 μM (MCF-7) and IC50 60.7 μM (NCI-H187) [40]  149 IC50 57.2 μM (KB), IC50 84.8 μM (MCF-7) and IC50 66.3 μM (NCI-H187) [40]  150 IC50 79.8 μM (KB), IC50 126.3 μM (MCF7) and IC50 61.1 μM (NCI-H187) [40]  151 IC50 45.2 μM (KB), IC50 16.6 μM (MCF-7) and IC50 70.2 μM (NCI-H187) [40]  152 IC50 33.9 μM (KB), IC50 67.3 μM (MCF7) and IC50 27.0 μM (NCI-H187) [40]  153 IC50 112.6 μM (KB), Inactive (MCF-7) and IC50 66.7 μM (NCI-H187) [40]  154 IC50 59.9 μM (KB), IC50 92.0 μM (MCF7) and IC50 28.6 μM (NCI-H187) [40]  155 IC50 43.3 μM (KB), IC50 129.7 μM (MCF-7) and IC50 32.3 μM (NCI-H187) [40]  158 LD90 20.0 μg/mL [5]  161 IC50 4.0 μM (KB), IC50 4.8 μM (MCF-7), IC50 4.2 μM (NCI-H187) and IC50 5.8 μM (Vero) [38]  162 IC50 9.6 μM (KB), IC50 12.9 μM (MCF-7), IC50 6.5 μM (NCI-H187) and IC50 8.8 μM (Vero) [38]  163 IC50 12.9 μM (KB), IC50 10.9 μM (MCF-7), IC50 11.4 μM (NCI-H187) and IC50 10.3 μM (Vero) [38]  164 IC50 10.5 μM (KB), IC50 15.2 μM (MCF-7), IC50 8.7 μM (NCI-H187) and IC50 11.7 μM (Vero) [38]  166 IC50 14.5 μM (KB), IC50 20.7 μM (MCF-7), IC50 11.5 μM (NCI-H187) and IC50 11.2 μM (Vero) [38]  167 IC50 24.1 μM (KB), IC50 21.0 μM (MCF-7), IC50 14.7 μM (NCI-H187) and IC50 17.9 μM (Vero) [38]  168 IC5010.5 μM (KB), IC50 11.9 μM (MCF-7), IC50 6.8 μM (NCI-H187) and IC50 18.2 μM (Vero) [38]  174-176 Inactive (KB, MCF-7, NCI-H187 and Vero) [38]  201-203 Inactive (KB and Vero) [7]  Plant extracts  n-Hexane extract of M. sinensis IC50 86.6 μg/mL (MCF-7), IC50 78.33 μg/mL (LU), IC50 36.72 μg/mL (Hep-G2) and IC50 82.04 μg/mL (KB) [37]  Ethyl acetate extract ofM. sinensis IC50 72.52 μg/mL (MCF-7), IC50 75.09 μg/mL (LU), IC50 42.50 μg/mL (Hep-G2)And IC50 59.13 μg/mL (KB) [37]  n-Butanol extract of M. sinensis IC50 > 128.0 μg/mL (MCF-7 and KB) [37]  n-Hexane extract of M. smithiae ED50 9.07 μg/mL (P-388), ED50 12.0 μg/mL (KB), ED50 8.53 μg/mL (Col2), ED50 1.16 μg/mL (MCF-7), ED50 11.98 μg/mL (Lu1), ED50 13.31 μg/mL (T24), ED50 11.6 μg/mL (ASK) and ED50 6.74 μg/mL (Hek293) [36]  Ethyl acetate extract ofM. smithiae ED50 2.07 μg/mL (P-388), ED50 5.45 μg/mL (KB), ED50 1.98 μg/mL (Col2), ED50 0.3 μg/mL (MCF-7), ED50 5.85 μg/mL (Lu1), ED50 3.29 μg/mL (T24), ED50 3.83 μg/mL (ASK) and ED50 < 4.0 μg/mL (Hek293) [36]  Methanol and acetone extracts ofM. smithiae Inactive (P-388, KB, Col2, MCF-7, Lu1, T24, ASK and Hek293) [36] T h e   b , c results derived from different models.Huong and partners (2004b) pointed out four flavonoids,75-76 and94-95, from VietnameseM. balansae plant not just to show their powerful capacities (IC50 < 5.0 μg/mL) in cytotoxic assay against the three cancer cell lines KB, Hep-G2, and RD, but also to emphasize that the introduction and modification of functional groups at carbon C-3, C-6, C-3′, and C-4′ were reasonable in the different results between pachypodol (95) and the remaining tested compounds75-76 and94 [30].We then moved on to the demonstration of the proper agents from another Vietnamese medicinal plant,M. sinensis.n-Hexane and ethyl acetate extracts of this plant were moderately or weakly active against the four cancer cell lines MCF-7, LU, Hep-G2, and KB (IC50 42.5-86.6 μg/mL); in particular, their secondary metabolite liriodenine (12) induced the strong IC50 values of 2.3-2.89 μg/mL towards MCF-7 and KB, butn-butanol extract and two isolated flavonoids, 3,5-dihydroxy-7,3′,4′-trimethoxyflavone (79) and 4′,6′-dihydroxy-2′,3′,4-trimethoxydihydrochalcone (107), did not show significant potency (IC50 > 128.0 μg/mL) [37]. Likewise, the weak-polar extracts of typen-hexane and ethyl acetate extracts of ThaiM. smithiaespecies generally revealed moderate cytotoxic results in the experiment with eight cell lines, P-388, KB, Col-2, MCF-7, Lu-1, T24, ASK, and Hek293, but better than the inactivation of the polar extracts of type acetone and methanol extracts [36]. It is worthy of note that ethyl acetate part and its isolated flavonoid ayanin (75) against MCF-7 with the IC50 values of 0.3-0.68 μg/mL were comparable to positive control ellipticine (IC50 0.37 μg/mL) [36].In a comparison between new dihydrobenzofuran neolignan 3′ methoxymiliumollin (134) and its analogs decurrenal (123), miliumollin (140), and miliumollinone (141) in the cytotoxic assay against the three cancer cell lines KB, MC7, and NCI-H187 (Table 3), methoxylation would lead to reducing the IC50 values but the modification of allyl group did not seem to be the way of positive signal [9]. In another case, with the same test to KB, MC7, and NCI-H187 cell lines, the cytotoxic activity of chemical constituents ofM. fragrans induced a clear arrangement as follows: 7S,8R-8.O.4′-neolignan143 (IC50 12.7-14.4 μg/mL) > dihydrobenzofuran neolignan131 (IC50 12.9-16.7 μg/mL) > 7R,8R-7.O.3′,8.O.4′-neolignan139 (IC50 16.7-23.8 μg/mL) > 7S,8R-7.O.3′,8.O.4′-neolignans124-125 and130(IC50 15.9-28.4 μg/mL) > flavan116 (inactive) [10].Now, it is pretty noticeable that uncommon bicyclic lactones velutinindimers A-D and F-H (161-164 and166-168) gave rise to a range of the IC50 values from 4.0 μM to 24.1 μM in inhibiting three cancer cell lines, KB, MCF-7, and NCI-H187, and Vero cell line, while three new styryl derivatives174-176 failed to do so [38]. As discussed above, leaf ofM. cuneata was renowned as a reservoir of the diverse classes of secondary metabolites, but there has been a discrepancy between them in the cytotoxic assay [7]. In detail, either alkaloids, amides, flavonoids, or lignans inactivated towards two cell lines, KB and Vero, only geranylated homogentisic acid (+)-miliusol (72) and took part in suppressing these two cell lines with the IC50 values of 10.2 ± 0.1 μM and 13.5 ± 0.5 μM, respectively.Phytochemical studies onMiliusaplants have reached certain successes with isolating and identifying the presence of geranylated homogentisic acids, but more than ever, these compounds were further set to justify the cytotoxicity.Isolated compounds33-37 possessed the cytotoxic activities against the four cell lines KB, MCF-7, NCI-H187, and Vero with IC50 values in the range of 5.8-40.4 μg/mL, and the failure of the two compounds38-39 (IC50 > 50.0 μg/mL) led to a hypothetical suggestion that the modification of double bond of geranyl unit would not be considered as a good method to promote the positive signal in assay [32].Twenty-two homogentisic acid derivatives, comprising (+)-miliusate (40), (+)-miliusol (72), and serial (+)-miliusanes I-XX (41-60), have been screened by the cytotoxic assay with seven cancer cell lines, KB, Lu1, Col2, LNCaP, MCF-7, HUVEC, and HL60, and the results were briefly summarized in Table 2 [14]. It is worth mentioning that in structure-biology relationship, at the dose of 20.0 μg/mL, (+)-miliusane V (45) was reported to be a nontoxic compound (IC50 > 55.0 μg/mL) due to acetyl amide group. When comparing between (+)-miliusate (40) and (+)-miliusane IX (49), at carbon C-2, carbonylation was better than hydroxylation, but the opposite phenomenon was observed between (+)-miliusane VIII (48) and (+)-miliusol (72) since hydroxy group transferred into carbonyl group at carbon C-5. In accordance with the above results, hydroxylation, carbonylation, and epoxidation occurred at double bond of geranyl units of (+)-miliusanes X-XVII (50-57); the cytotoxicity did not enhance. Last but not least, γ-lactone ring opening, such as in compounds (+)-miliusanes XVIII-XIX (58-59), was shown not to render the cytotoxicity.As part of the ongoing effort to improve the efficacy of miliusane derivatives, recently, nineteen isolated compounds, (+)-miliusate (40), (+)-miliusanes I-II, IX, XIV-XV, XVII, XXI-XXI (41-42,49,54-55,57, 61-71), and (+)-miliusol (72), were continued to submit the cytotoxic assay with three cancer cell lines HCT116, A375, and A549 [13]. The results showed the positive signals when compounds40-42,54-55,57,68, especially (+)-miliusate (40), and (+)-miliusol (72) were demonstrated to be the most active with the IC50 values of 1.0-5.0 μM.


### 4.2. Anticancer Activity

Anticancer experiments have been so far designated as a consequence of cytotoxicity. With the GI50 values in the range of 0.03-4.79 μM, three geranylated derivatives of homogentisic acids, (+)-miliusate (40), (+)-miliusane I (41), and (+)-miliusol (72), showed the potential antitumor activities towards NCI-60 panel of human cancer cell lines, but were more active with HCT116 cell line [13]. In a comprehensive analysis, the main component ofMiliusa plants, namely, (+)-miliusol (72), was highly recommended to anticancer drugs development. At the end of 21st day ofin vivo anticancer treatment, this compound (20.0 mg/kg) induced the decrease in average size of excised HCT116 xenograft mouse tumor up to 72.7%, and the mechanism may be due to p21-dependent induction of cellular senescence rather than apoptosis [13].


### 4.3. Antimalarial Activity

With regard to antimalarial activities againstPlasmodium falciparum strains TM4 and K1, the IC50 values established a consistent arrangement as follows: standard compound cycloguanil (IC50 0.08 ± 0.01 μM and IC50 31.0 ± 8.4 μM) > geranylated homogentisic acid (+)-miliusol (72) (IC50 11.1 ± 2.0 μM and IC50 9.1 ± 3.1 μM) > new oxo-protoberberine alkaloids18-22, flavones76 and87, and amides201 and203 (IC50 19.3-41.4 μM and IC50 10.8-54.9 μM) > flavones83 and95, lignan119 and amide202(inactive) [7]. It should be noted that among the four flavones76,83,87, and95, methylation at 5-OH and methoxylation at carbon C-6 can be responsible for promoting antimalaria, in contrast to the phenomenon dioxane-cyclization between two hydroxyl groups at C-3′ and C-4′, whereas hydroxylation and methoxylation atmeta-position of caffeoyl unit induced the potential differences among the three amides201-203.In addition to antimalarial assay, two known isolated compounds33-34 and new one miliusanone A (36) inhibited the growth ofP. falciparum with the IC50 values of 3.3-3.9 μg/mL but better than those of analogs miliusanone A (37) (IC50 5.2 μg/mL), miliusanal (35), and miliusanones C-D (38-39) (IC50 > 10 μg/mL) [32]. From these data, it was also concluded that among the four geranylated homogentisic acid derivatives33-34 and36-37, the number of ester groups in the structure seemed to be the main for the outcome.Serial new acetogenins cananginones A-I (147-150 and152-155) failed to inhibitP. falciparum except for cananginone E (151) (IC50 24.4 μM) [40]. Comparing between the structure151 and the close group of compounds152 and154-155, dihydroxylation of double bonds and methylene reduction would not be facilitated.Three new bulk styryl derivatives, velutinindimers A-C (174-175), established better IC50 values in the range of 5.4-6.4 μM towardsP. falciparumthan new unique bicyclic lactones velutinones B-D, G, and H (162-164 and167-168) (IC50 7.3-10.0 μM) [38].


### 4.4. Antifungal and Antimycobacterial Activities

In the search for natural products against DNA repair mutant in the yeast strainSaccharomyces cerevisiae, the MeCOEt extract ofM. CF.banacea root showed inhibitedrad 52.top 1 (IC12 2000 μg/mL), but failed to do so withrad52 andrad+ (IC12 > 8000 μg/mL) [4]. In the meantime, new alkaloid 10-hydroxyliriodenine (7) and positive control camptothecin afforded the respective IC12 values of 72 μg/mL and >20 μg/mL in suppressingrad 52.top 1, being better than that of 10-methoxyliriodenine (14) (IC12 113 μg/mL).The MIC values ranging from 4.0μg/mL to >128 μg/mL were the results when using chalcone pashanone (109) and flavanone 5-hydroxy-6,7-dimethoxyflavanone (110) against thirteen human pathogenic fungi,Candida albicans ATCC10231,Candida kruseiATCC6258,Candida lusitaniae ATCC42720,Candida tropicalis ATCC13803,Cryptococcus gattiiR265,Cryptococcus gattii WM276,Cryptococcus neoformansJEC21,Cryptococcus neoformans ATCC36556,Cryptococcus neoformansvar.grubii H99,Aspergillus fumigatusATCC16424, andTrichophyton mentagrophytes ATCC9533 [6].The effect of new cananginones H-I (154-155) on fungalC. albicanshas been shown to be associated with the IC50 values of 75.2 μM and 37.4 μM, respectively, but new acetogenins cananginones A-G (147-153) did not appear active [40]. Herein, the reason is opposite to antimalarial analysis when four structures151-152 and154-155 were considerably compared.The global health problem in developing countries is becoming increasingly involved in growing and expanding of microbacteria. Historical records have accumulated evidence showing that the use of traditional antibiotics, which are derived from synthetic substances, is always accompanied by a long duration of treatment, high cost, and drug resistance [48]. Therefore, calls for new antibiotic drugs from natural sources in the fight against multidrug-resistant bacteria are always strategy.In a short communication, various components fromM. tomentosa species suppressed the growth of several kinds of bacteria and fungi, but the most significant finding is that leaf volatile oil extract reduced the growth of bacteriumBacillus subtilisNCIM 2250 and fungalC. albicans NCIM 3471 with the same MIC value of 0.62 mg/mL, being better than those of leaf aqueous extract (2.5 mg/mL and 5.0 mg/mL, respectively) [49].Acetogenin A (145) and goniothalamusin (158) are associated with the moderate antibacterial activity with diameters of the inhibitory zone of 9-14 mm against positive Gram bacteriaBacillus cereus,Staphylococcus aureus, andStreptococcusβ-haemolyticusand 9-11 nm against negative Gram bacteriaSalmonella typhi,Shigella flexneri, andShigella dysenteriae, whereas acetogenin A (146) only influencedB. cereuswith diameter zone of 11 mm [5].The MIC values ranged from 32.0 to 64.0μg/mL, which were the moderate antibacterial result of two geranylated homogentisic acids,33 and35, repellent positive Gram bacteriaB. cereus DMST 5040,S. aureus DMST 8013, and methicillin resistantS. aureus. Meanwhile, two other geranylated homogentisic acids,34and36, and two styryls,171 and175, were only found to be associated with the MIC values of 64.0-128.0 μg/mL againstB. cereus DMST 5040 [32]. It was, therefore, concluded that geranylated homogentisic acids seemed to be better candidates for this problem rather than styryl derivatives.At the same time, compound33 revealed the MIC value of 50 μg/mL to treatMycobacterium tuberculosis H37Ra compared with that of the similar structures34-39 (MIC > 50 μg/mL) [32]. Apparently, substituting groups R1 and R2 demonstrated the great role affecting the results.Two unique bicyclic lactones,161-162, resisted the growth ofM. tuberculosis with the MIC values of 43.4 μM and 82.1 μM, respectively, but analogs163-168 showed no activity. It is possible to note that epoxidation and hydroxylation would not be good circumstances to have positive signals in the activity [38].


### 4.5. Anti-Inflammatory Activity

Inflammation can be seen as a part of the complex biological response of the body tissues to harmful stimuli, such as irradiation, physical damage, metabolic overload, or infection [20]. Nowadays, modern diseases, for instance, cardiovascular and neurodegenerative disorders, are closely related to inflammation. Suppressing NO production is recognized to be a useful strategy for this problem.On the screening of anti-inflammatory activity, by using mode of lipopolysaccharides (LPS) (1.0μg/mL)-induced NO production in microglial RAW 264.7 cells, megastigmane glycosides milbasides A-C (179-181), alcohols β-D-glucopyranoside (Z)-3-hexenol (205), and (L)-guaiacyl glycerol 2′-O-β-D-glucopyranoside (208), at a concentration of 20.0 μM, together with flavan (−)-epicatechin (116) and megastigmane glucoside myrsinionoside D (184), at a concentration of 40.0 μM, indicated potent inhibitory activity comparable with or better than positive control sulfuretin (81.3 ± 4.9% at 20.0 μM) [11].Because of glycosylation, NO inhibitory capacity compound208 was generated 2.0-2.5 times higher than those oferythro- andthreo-guaiacylglycerol (206-207) (48.4 ± 3.9%) [11].


### 4.6. Antiherpetic Activity

At the dose of 100μg/mL, methanol extracts from stem and leaf ofM. fragrans showed the IC50 values of 60-80 μg/mL in the antiherpetic experiment against HSV-1 and HSV-2. Meanwhile, in contrast to the inactive results of116-118,120-121,124,128-130,135,139, and143-144, (+)-4-O-demethyleusiderin C (125) and licarin A (131) were found to possess the same IC50 values of 62.5-66.7 μg/mL (HSV-1) and 87.5 μg/mL (HSV-2) [9]. It was figured out that 7S,8R-7.O.3′,8.O.4′-neolignans should be the best choice for this model. Furthermore, by comparing124-125 and129-130, their antiherpetic outcomes closely depended on two functional groups, R1 and R2 (Figure 4).


### 4.7. Antioxidant Activity

Although phytochemical investigation ofM. wayanadica species has not yet been performed extensively, its ethanol leaf extract was observed to be equivalent to or better than positive controls in antioxidant assays. For instance, in DPPH assay, the IC50 value of 465 μg/mL arising fromM. wayanadica ethanol leaf extract was comparable with those of standard compounds BHT (570 μg/mL) and BHA (615 μg/mL); with regard to the ferric reducing antioxidant examination, the IC50 values for these three objects reached 600 μg/mL, 835 μg/mL, and 870 μg/mL, respectively [50].


### 4.8. Enzyme Acetylcholine Inhibitory Activity

To date, only one research dealt with the use of chemical constituents fromM. thorelii species exploring the potency ofMiliusa secondary metabolites in acetylcholinesterase inhibitory activity. The results pointed out that alkaloids (the inhibitory capacity of new oxo-protoberberines23-24 and known one28 reached the significant range of 27.93%-50.17%) were promising agents rather than flavonoids (the inhibitory percentages of <10%-38.68% were for80-83,85-86,88-91,93,95-99, and101-102) or amides (tested compounds201 and203 were inactive, <10%) [32].


### 4.9. Cardiac Activity

Chrysosplenol C (77), a flavonol, isolated fromM. balansae, proved to be an essential backbone to induce a positive inotropic effect on rat ventricular myocytes [12]. This compound caused the contractive percentage of ventricular cell and the active percentage of cardiac myosin ATPase up to 53.0 ± 4.07% at 50 μM and 28.1 ± 1.20% at 10 μM, respectively, compared with those of positive control omecamtiv mecarbil [59.3 ± 2.60% at 400 nM and 80.4 ± 2.89% at 10 μM, respectively] [12].


## 4.1. Cytotoxic Activity

The plants of genusMiliusa included sets of variously useful isolated components to the 得 experimentally cytotoxic targets. In the review of all conditions, the cytotoxic results were briefly summarized in Table 3. Earlier report in 2000 by Jumana and partners mentioned the cytotoxicity of constituents fromM. velutina species; the LC90 results of tested compounds may run as acetogenin A (145) (LC90 7.1 μg/mL) > acetogenin B (146) (LC90 14.1 μg/mL) > positive control vincristine (LC90 15.0 μg/mL) > goniothalamusin (158) (LC90 20.0 μg/mL) [5]. Nine new acetogenins cananginones A-I (147-155) were found to possess the weak IC50 values of 16.6-129.7 μM or be inactive in the cytotoxic assay against three cancer cell lines KB, MCF7, and NCI-H187, when compared to those of reference compound doxorubicin (IC50 0.46-1.05 μM) [40].Table 3
Cytotoxic results ofMiliusa components.
No Inhibitory concentrations (cell lines) References Isolated compound  12 IC50 2.89 μg/mL (MCF-7), IC50 6.66 μg/mL (LU), IC50 5.23 μg/mL (Hep-G2) and IC50 2.30 μg/mL (KB) [37]  18-22 Inactive (KB and Vero) [7]  33 IC50 26.5 μg/mL (KB), IC50 32.7 μg/mL (MCF-7), IC50 5.8 μg/mL (NCI-H187) and IC50 6.3 μg/mL (Vero) [32]  34 IC50 11.8 μg/mL (KB), IC50 > 50.0 μg/mL (MCF-7), IC50 6.1 μg/mL (NCI-H187) and IC50 17.7 μg/mL (Vero) [32]  35 IC50 9.3 μg/mL (KB), IC50 3.6 μg/mL (MCF-7), IC50 40.4 μg/mL (NCI-H187) and IC50 39.1 μg/mL (Vero) [32]  36 IC50 11.9 μg/mL (KB), IC50 23.2 μg/mL (MCF-7), IC50 6.1 μg/mL (NCI-H187) and IC50 16.1 μg/mL (Vero) [32]  37 IC50 17.9 μg/mL (KB), IC50 26.4 μg/mL (MCF-7), IC50 6.2 μg/mL (NCI-H187) and IC50 5.8 μg/mL (Vero) [32]  38 IC50 > 50.0 μg/mL (KB, MCF-7, NCI-H187, Vero) [32]  39 IC50 > 50.0 μg/mL (KB, MCF-7, NCI-H187, Vero) [32]  40 IC50 1.18 μg/mL (KB), IC50 2.02 μg/mL (Lu1), IC50 1.56 μg/mL (Col2), IC50 3.18 μg/mL (LNCaP), IC50 3.58 μg/mL (MCF-7), IC50 2.89 μg/mL (HUVEC), IC50 0.32 μg/mL (HL60), IC50 2.70 ± 0.09 μM (HCT116), IC50 1.67 ± 0.11 μM (A375) and IC50 6.97 ± 0.16 μM (A549) [13, 14]  41 IC50 1.40 μg/mL (KB), IC50 2.86 μg/mL (Lu1), IC50 2.92 μg/mL (Col2), IC50 5.06 μg/mL (LNCaP), IC50 2.23 μg/mL (MCF-7), IC50 1.79 μg/mL (HUVEC), IC50 0.45 μg/mL (HL60), IC50 3.50 ± 0.02 μM (HCT116), IC50 3.70 ± 0.11 μM (A375) and IC50 4.36 ± 0.40 μM (A549) [13, 14]  42 IC50 5.45 μg/mL (KB), IC50 5.80 μg/mL (Lu1), IC50 9.40 μg/mL (Col2), IC50 19.64 μg/mL (LNCaP), IC50 21.34 μg/mL (MCF-7), IC50 6.55 μg/mL (HUVEC), IC50 1.73 μg/mL (HL60), IC50 17.2 ± 1.86 μM (HCT116), IC50 9.86 ± 0.19 μM (A375) and IC50 18.4 ± 0.35 μM (A549) [13, 14]  43 IC50 1.18 μg/mL (KB), IC50 4.84 μg/mL (Lu1), IC50 4.29 μg/mL (Col2), IC50 5.06 μg/mL (LNCaP), IC50 2.61 μg/mL (MCF-7) and IC50 0.56 μg/mL (HL60) [14]  44 IC50 32.17 μg/mL (KB), IC50 60.43 μg/mL (Lu1), IC50 38.45 μg/mL (Col2), IC50 > 62.0 μg/mL (LNCaP), IC50 15.78 μg/mL (MCF-7) and IC50 18.66 μg/mL (HL60) [14]  45 IC50 > 55.0 μg/mL (KB, Lu1, Col2, LNCaP and MCF-7) and IC50 52.29 μg/mL (HL60) [14]  46 IC50 3.97 μg/mL (KB), IC50 6.61 μg/mL (Lu1), IC50 4.23 μg/mL (Col2), IC50 5.29 μg/mL (LNCaP) and IC50 4.76 μg/mL (MCF-7) [14]  47 IC50 5.82 μg/mL (KB), IC50 6.16 μg/mL (Lu1), IC50 3.70 μg/mL (Col2), IC50 5.82 μg/mL (LNCaP) and IC50 6.08 μg/mL (MCF-7) [14]  48 IC50 47.35 μg/mL (KB), IC50 63.58 μg/mL (Lu1), IC50 33.44 μg/mL (Col2), IC50 43.38 μg/mL (LNCaP), IC50 26.42 μg/mL (MCF-7) and IC50 > 10.9 μg/mL (HUVEC) [14]  49 IC50 > 57.4 μg/mL (KB, Lu1, LNCaP), IC50 46.01 μg/mL (Col2), IC50 52.56 μg/mL (MCF-7), IC50 13.3 ± 0.62 μM (HCT116), IC50 7.24 ± 0.81 μM (A375) and IC50 18.3 ± 2.54 μM (A549) [13, 14]  50/51 IC50 5.22 μg/mL (KB), IC50 21.44 μg/mL (Lu1), IC50 8.03 μg/mL (Col2), IC50 29.56 μg/mL (LNCaP), IC50 5.03 μg/mL (MCF-7) and IC50 3.28 μg/mL (HL60) [14]  52/53 IC50 54.97 μg/mL (KB), IC50 9.31 μg/mL (Lu1), IC50 13.43 μg/mL (Col2), IC50 51.82 μg/mL (LNCaP) and IC50 12.18 μg/mL (MCF-7) [14]  54/55 IC50 5.28 μg/mL (KB), IC50 7.46 μg/mL (Lu1), IC50 5.36 μg/mL (Col2), IC50 27.62 μg/mL (LNCaP), IC50 10.06 μg/mL (MCF-7), IC50 3.30 ± 0.06 μM (HCT116), IC50 3.38 ± 0.09 μM (A375) and IC50 10.4 ± 0.32 μM (A549) [13, 14]  56 IC50 6.11 μg/mL (KB), IC50 19.94 μg/mL (Lu1), IC50 3.89 μg/mL (Col2), IC50 6.11 μg/mL (LNCaP) and IC50 6.39 μg/mL (MCF-7) [14]  57 IC50 6.71 μg/mL (KB), IC50 14.94 μg/mL (Lu1), IC50 9.48 μg/mL (Col2), IC50 23.95 μg/mL (LNCaP), IC50 10.99 μg/mL (MCF-7), IC50 4.20 ± 0.30 μM (HCT116), IC50 4.25 ± 0.05 μM (A375) and IC50 20.8 ± 1.24 μM (A549) [13, 14]  58 IC50 3.07 μg/mL (KB), IC50 1.82 μg/mL (Lu1), IC50 2.26 μg/mL (Col2), IC50 2.41 μg/mL (LNCaP), IC50 3.01 μg/mL (MCF-7) and IC50 0.63 μg/mL (HL60) [14]  59 IC50 2.61 μg/mL (KB), IC50 1.82 μg/mL (Lu1), IC50 2.01 μg/mL (Col2), IC50 1.73 μg/mL (LNCaP) and IC50 2.26 μg/mL (MCF-7) [14]  60 IC50 > 59.0 μg/mL (KB, Lu1, Col2, LNCaP and MCF-7) and IC50 57.01 μg/mL (HL60) [14]  61 IC50 > 65.0 μg/mL (HCT116, A375, A549) [13]  62/63 IC50 9.80 ± 0.51 μM (HCT116), IC50 6.96 ± 0.23 μM (A375) and IC50 24.3 ± 1.42 μM (A549) [13]  64/65 IC50 > 52.9 μM (HCT116, A375 and A549) [13]  66/67 IC50 > 55.0 μM (HCT116, A375 and A549) [13]  68 IC50 4.10 ± 0.13 μM (HCT116), IC50 3.60 ± 0.33 μM (A375) and IC50 7.15 ± 0.18 μM (A549) [13]  69 IC50 > 57.5 μM (HCT116, A375 and A549) [13]  70 IC50 13.0 ± 0.17 μM (HCT116), IC50 10.4 ± 0.66 μM (A375) and IC50 24.5 ± 1.56 μM (A549) [13]  71 IC50 18.3 ± 0.59 μM (HCT116), IC50 11.6 ± 1.45 μM (A375) and IC50 18.0 ± 2.80 μM (A549) [13]  72 IC50 10.2 ± 0.1 μM (KB)b, IC50 13.5 ± 0.5 μM (Vero), IC50 2.00 ± 0.16 μM (HCT116), IC50 1.50 ± 0.15 μM (A375), IC50 2.45 ± 0.24 μM (A549), IC50 1.18 μg/mL (KB)c, IC50 1.64 μg/mL (Lu1), IC50 1.35 μg/mL (Col2), IC50 1.78 μg/mL (LNCaP), IC50 3.09 μg/mL (MCF-7), IC50 1.32 μg/mL (HUVEC) and IC50 0.66 μg/mL (HL60) [7]b; [13], [14]c  75 ED50 3.6 μg/mL (P-388), ED50 0.76 μg/mL (Col2), ED50 0.68 μg/mL (MCF-7)ED50 16.08 μg/mL (ASK), ED50 2.81 μg/mL (Hek293) and Inactive (KB, Lu-1 and T24) [36]  76 IC50 4.6 μg/mL (KB), IC50 0.93 μg/mL (Hep-G2) and IC50 > 5.0 μg/mL (RD) [35]  77 IC50 4.3 μg/mL (KB), IC50 0.57 μg/mL (Hep-G2) and IC50 2.09 μg/mL (RD) [35]  79 and 107 IC50 > 128.0 μg/mL (MCF-7, LU, Hep-G2 and KB) [37]  83 and 87 Inactive (KB and Vero) [7]  94 > 5.0μg/mL (KB and RD) and 1.5 μg/mL (Hep-G2) [35]  95 IC50 0.7 μg/mL (KB), IC50 0.55 μg/mL (Hep-G2) and IC50 3.01 μg/mL (RD) [35]  116 Inactive (KB, MCF-7 and NCI-H187) [9]  119 Inactive (KB and Vero) [7]  123 IC50 137.4 μM (KB), IC50 169.1 μM (MCF-7) and IC50 94.7 μM (NCI-H178) [10]  124 IC50 20.0 μg/mL (KB), IC50 21.0 μg/mL (MCF-7) and IC50 17.1 μg/mL (NCI-H178) [9]  125 IC50 17.9 μg/mL (KB), IC50 28.4 μg/mL (MCF-7) and IC50 15.9 μg/mL (NCI-H178) [9]  130 IC50 18.4 μg/mL (KB), IC50 22.6 μg/mL (MCF-7) and IC50 20.6 μg/mL (NCI-H178) [9]  131 IC50 12.9 μg/mL (KB), IC50 45.6 μg/mL (MCF-7) and IC50 16.7 μg/mL (NCI-H178) [9]  134 IC50 31.4 μM (KB), IC50 56.2 μM (MCF-7) and IC50 61.3 μM (NCI-H178) [10]  139 IC50 23.8 μg/mL (KB), IC50 24.4 μg/mL (MCF-7) and IC50 16.7 μg/mL (NCI-H178) [9]  140 IC50 27.2 μM (KB), IC50 71.9 μM (MCF-7) and IC50 95.3 μM (NCI-H178) [10]  141 IC50 95.9 μM (KB), IC50 142.7 μM (MCF-7) and IC50 115.9 μM (NCI-H178) [10]  143 IC50 14.4 μg/mL (KB), IC50 13.0 μg/mL (MCF-7) and IC50 12.7 μg/mL (NCI-H178) [9]  145 LD90 7.1 μg/mL [5]  146 LD90 14.1 μg/mL [5]  147 IC50 99.0 μM (KB), Inactive (MCF7) and IC50 48.9 μM (NCI-H187) [40]  148 IC50 67.4 μM (KB), IC50 93.7 μM (MCF-7) and IC50 60.7 μM (NCI-H187) [40]  149 IC50 57.2 μM (KB), IC50 84.8 μM (MCF-7) and IC50 66.3 μM (NCI-H187) [40]  150 IC50 79.8 μM (KB), IC50 126.3 μM (MCF7) and IC50 61.1 μM (NCI-H187) [40]  151 IC50 45.2 μM (KB), IC50 16.6 μM (MCF-7) and IC50 70.2 μM (NCI-H187) [40]  152 IC50 33.9 μM (KB), IC50 67.3 μM (MCF7) and IC50 27.0 μM (NCI-H187) [40]  153 IC50 112.6 μM (KB), Inactive (MCF-7) and IC50 66.7 μM (NCI-H187) [40]  154 IC50 59.9 μM (KB), IC50 92.0 μM (MCF7) and IC50 28.6 μM (NCI-H187) [40]  155 IC50 43.3 μM (KB), IC50 129.7 μM (MCF-7) and IC50 32.3 μM (NCI-H187) [40]  158 LD90 20.0 μg/mL [5]  161 IC50 4.0 μM (KB), IC50 4.8 μM (MCF-7), IC50 4.2 μM (NCI-H187) and IC50 5.8 μM (Vero) [38]  162 IC50 9.6 μM (KB), IC50 12.9 μM (MCF-7), IC50 6.5 μM (NCI-H187) and IC50 8.8 μM (Vero) [38]  163 IC50 12.9 μM (KB), IC50 10.9 μM (MCF-7), IC50 11.4 μM (NCI-H187) and IC50 10.3 μM (Vero) [38]  164 IC50 10.5 μM (KB), IC50 15.2 μM (MCF-7), IC50 8.7 μM (NCI-H187) and IC50 11.7 μM (Vero) [38]  166 IC50 14.5 μM (KB), IC50 20.7 μM (MCF-7), IC50 11.5 μM (NCI-H187) and IC50 11.2 μM (Vero) [38]  167 IC50 24.1 μM (KB), IC50 21.0 μM (MCF-7), IC50 14.7 μM (NCI-H187) and IC50 17.9 μM (Vero) [38]  168 IC5010.5 μM (KB), IC50 11.9 μM (MCF-7), IC50 6.8 μM (NCI-H187) and IC50 18.2 μM (Vero) [38]  174-176 Inactive (KB, MCF-7, NCI-H187 and Vero) [38]  201-203 Inactive (KB and Vero) [7]  Plant extracts  n-Hexane extract of M. sinensis IC50 86.6 μg/mL (MCF-7), IC50 78.33 μg/mL (LU), IC50 36.72 μg/mL (Hep-G2) and IC50 82.04 μg/mL (KB) [37]  Ethyl acetate extract ofM. sinensis IC50 72.52 μg/mL (MCF-7), IC50 75.09 μg/mL (LU), IC50 42.50 μg/mL (Hep-G2)And IC50 59.13 μg/mL (KB) [37]  n-Butanol extract of M. sinensis IC50 > 128.0 μg/mL (MCF-7 and KB) [37]  n-Hexane extract of M. smithiae ED50 9.07 μg/mL (P-388), ED50 12.0 μg/mL (KB), ED50 8.53 μg/mL (Col2), ED50 1.16 μg/mL (MCF-7), ED50 11.98 μg/mL (Lu1), ED50 13.31 μg/mL (T24), ED50 11.6 μg/mL (ASK) and ED50 6.74 μg/mL (Hek293) [36]  Ethyl acetate extract ofM. smithiae ED50 2.07 μg/mL (P-388), ED50 5.45 μg/mL (KB), ED50 1.98 μg/mL (Col2), ED50 0.3 μg/mL (MCF-7), ED50 5.85 μg/mL (Lu1), ED50 3.29 μg/mL (T24), ED50 3.83 μg/mL (ASK) and ED50 < 4.0 μg/mL (Hek293) [36]  Methanol and acetone extracts ofM. smithiae Inactive (P-388, KB, Col2, MCF-7, Lu1, T24, ASK and Hek293) [36] T h e   b , c results derived from different models.Huong and partners (2004b) pointed out four flavonoids,75-76 and94-95, from VietnameseM. balansae plant not just to show their powerful capacities (IC50 < 5.0 μg/mL) in cytotoxic assay against the three cancer cell lines KB, Hep-G2, and RD, but also to emphasize that the introduction and modification of functional groups at carbon C-3, C-6, C-3′, and C-4′ were reasonable in the different results between pachypodol (95) and the remaining tested compounds75-76 and94 [30].We then moved on to the demonstration of the proper agents from another Vietnamese medicinal plant,M. sinensis.n-Hexane and ethyl acetate extracts of this plant were moderately or weakly active against the four cancer cell lines MCF-7, LU, Hep-G2, and KB (IC50 42.5-86.6 μg/mL); in particular, their secondary metabolite liriodenine (12) induced the strong IC50 values of 2.3-2.89 μg/mL towards MCF-7 and KB, butn-butanol extract and two isolated flavonoids, 3,5-dihydroxy-7,3′,4′-trimethoxyflavone (79) and 4′,6′-dihydroxy-2′,3′,4-trimethoxydihydrochalcone (107), did not show significant potency (IC50 > 128.0 μg/mL) [37]. Likewise, the weak-polar extracts of typen-hexane and ethyl acetate extracts of ThaiM. smithiaespecies generally revealed moderate cytotoxic results in the experiment with eight cell lines, P-388, KB, Col-2, MCF-7, Lu-1, T24, ASK, and Hek293, but better than the inactivation of the polar extracts of type acetone and methanol extracts [36]. It is worthy of note that ethyl acetate part and its isolated flavonoid ayanin (75) against MCF-7 with the IC50 values of 0.3-0.68 μg/mL were comparable to positive control ellipticine (IC50 0.37 μg/mL) [36].In a comparison between new dihydrobenzofuran neolignan 3′ methoxymiliumollin (134) and its analogs decurrenal (123), miliumollin (140), and miliumollinone (141) in the cytotoxic assay against the three cancer cell lines KB, MC7, and NCI-H187 (Table 3), methoxylation would lead to reducing the IC50 values but the modification of allyl group did not seem to be the way of positive signal [9]. In another case, with the same test to KB, MC7, and NCI-H187 cell lines, the cytotoxic activity of chemical constituents ofM. fragrans induced a clear arrangement as follows: 7S,8R-8.O.4′-neolignan143 (IC50 12.7-14.4 μg/mL) > dihydrobenzofuran neolignan131 (IC50 12.9-16.7 μg/mL) > 7R,8R-7.O.3′,8.O.4′-neolignan139 (IC50 16.7-23.8 μg/mL) > 7S,8R-7.O.3′,8.O.4′-neolignans124-125 and130(IC50 15.9-28.4 μg/mL) > flavan116 (inactive) [10].Now, it is pretty noticeable that uncommon bicyclic lactones velutinindimers A-D and F-H (161-164 and166-168) gave rise to a range of the IC50 values from 4.0 μM to 24.1 μM in inhibiting three cancer cell lines, KB, MCF-7, and NCI-H187, and Vero cell line, while three new styryl derivatives174-176 failed to do so [38]. As discussed above, leaf ofM. cuneata was renowned as a reservoir of the diverse classes of secondary metabolites, but there has been a discrepancy between them in the cytotoxic assay [7]. In detail, either alkaloids, amides, flavonoids, or lignans inactivated towards two cell lines, KB and Vero, only geranylated homogentisic acid (+)-miliusol (72) and took part in suppressing these two cell lines with the IC50 values of 10.2 ± 0.1 μM and 13.5 ± 0.5 μM, respectively.Phytochemical studies onMiliusaplants have reached certain successes with isolating and identifying the presence of geranylated homogentisic acids, but more than ever, these compounds were further set to justify the cytotoxicity.Isolated compounds33-37 possessed the cytotoxic activities against the four cell lines KB, MCF-7, NCI-H187, and Vero with IC50 values in the range of 5.8-40.4 μg/mL, and the failure of the two compounds38-39 (IC50 > 50.0 μg/mL) led to a hypothetical suggestion that the modification of double bond of geranyl unit would not be considered as a good method to promote the positive signal in assay [32].Twenty-two homogentisic acid derivatives, comprising (+)-miliusate (40), (+)-miliusol (72), and serial (+)-miliusanes I-XX (41-60), have been screened by the cytotoxic assay with seven cancer cell lines, KB, Lu1, Col2, LNCaP, MCF-7, HUVEC, and HL60, and the results were briefly summarized in Table 2 [14]. It is worth mentioning that in structure-biology relationship, at the dose of 20.0 μg/mL, (+)-miliusane V (45) was reported to be a nontoxic compound (IC50 > 55.0 μg/mL) due to acetyl amide group. When comparing between (+)-miliusate (40) and (+)-miliusane IX (49), at carbon C-2, carbonylation was better than hydroxylation, but the opposite phenomenon was observed between (+)-miliusane VIII (48) and (+)-miliusol (72) since hydroxy group transferred into carbonyl group at carbon C-5. In accordance with the above results, hydroxylation, carbonylation, and epoxidation occurred at double bond of geranyl units of (+)-miliusanes X-XVII (50-57); the cytotoxicity did not enhance. Last but not least, γ-lactone ring opening, such as in compounds (+)-miliusanes XVIII-XIX (58-59), was shown not to render the cytotoxicity.As part of the ongoing effort to improve the efficacy of miliusane derivatives, recently, nineteen isolated compounds, (+)-miliusate (40), (+)-miliusanes I-II, IX, XIV-XV, XVII, XXI-XXI (41-42,49,54-55,57, 61-71), and (+)-miliusol (72), were continued to submit the cytotoxic assay with three cancer cell lines HCT116, A375, and A549 [13]. The results showed the positive signals when compounds40-42,54-55,57,68, especially (+)-miliusate (40), and (+)-miliusol (72) were demonstrated to be the most active with the IC50 values of 1.0-5.0 μM.


## 4.2. Anticancer Activity

Anticancer experiments have been so far designated as a consequence of cytotoxicity. With the GI50 values in the range of 0.03-4.79 μM, three geranylated derivatives of homogentisic acids, (+)-miliusate (40), (+)-miliusane I (41), and (+)-miliusol (72), showed the potential antitumor activities towards NCI-60 panel of human cancer cell lines, but were more active with HCT116 cell line [13]. In a comprehensive analysis, the main component ofMiliusa plants, namely, (+)-miliusol (72), was highly recommended to anticancer drugs development. At the end of 21st day ofin vivo anticancer treatment, this compound (20.0 mg/kg) induced the decrease in average size of excised HCT116 xenograft mouse tumor up to 72.7%, and the mechanism may be due to p21-dependent induction of cellular senescence rather than apoptosis [13].


## 4.3. Antimalarial Activity

With regard to antimalarial activities againstPlasmodium falciparum strains TM4 and K1, the IC50 values established a consistent arrangement as follows: standard compound cycloguanil (IC50 0.08 ± 0.01 μM and IC50 31.0 ± 8.4 μM) > geranylated homogentisic acid (+)-miliusol (72) (IC50 11.1 ± 2.0 μM and IC50 9.1 ± 3.1 μM) > new oxo-protoberberine alkaloids18-22, flavones76 and87, and amides201 and203 (IC50 19.3-41.4 μM and IC50 10.8-54.9 μM) > flavones83 and95, lignan119 and amide202(inactive) [7]. It should be noted that among the four flavones76,83,87, and95, methylation at 5-OH and methoxylation at carbon C-6 can be responsible for promoting antimalaria, in contrast to the phenomenon dioxane-cyclization between two hydroxyl groups at C-3′ and C-4′, whereas hydroxylation and methoxylation atmeta-position of caffeoyl unit induced the potential differences among the three amides201-203.In addition to antimalarial assay, two known isolated compounds33-34 and new one miliusanone A (36) inhibited the growth ofP. falciparum with the IC50 values of 3.3-3.9 μg/mL but better than those of analogs miliusanone A (37) (IC50 5.2 μg/mL), miliusanal (35), and miliusanones C-D (38-39) (IC50 > 10 μg/mL) [32]. From these data, it was also concluded that among the four geranylated homogentisic acid derivatives33-34 and36-37, the number of ester groups in the structure seemed to be the main for the outcome.Serial new acetogenins cananginones A-I (147-150 and152-155) failed to inhibitP. falciparum except for cananginone E (151) (IC50 24.4 μM) [40]. Comparing between the structure151 and the close group of compounds152 and154-155, dihydroxylation of double bonds and methylene reduction would not be facilitated.Three new bulk styryl derivatives, velutinindimers A-C (174-175), established better IC50 values in the range of 5.4-6.4 μM towardsP. falciparumthan new unique bicyclic lactones velutinones B-D, G, and H (162-164 and167-168) (IC50 7.3-10.0 μM) [38].


## 4.4. Antifungal and Antimycobacterial Activities

In the search for natural products against DNA repair mutant in the yeast strainSaccharomyces cerevisiae, the MeCOEt extract ofM. CF.banacea root showed inhibitedrad 52.top 1 (IC12 2000 μg/mL), but failed to do so withrad52 andrad+ (IC12 > 8000 μg/mL) [4]. In the meantime, new alkaloid 10-hydroxyliriodenine (7) and positive control camptothecin afforded the respective IC12 values of 72 μg/mL and >20 μg/mL in suppressingrad 52.top 1, being better than that of 10-methoxyliriodenine (14) (IC12 113 μg/mL).The MIC values ranging from 4.0μg/mL to >128 μg/mL were the results when using chalcone pashanone (109) and flavanone 5-hydroxy-6,7-dimethoxyflavanone (110) against thirteen human pathogenic fungi,Candida albicans ATCC10231,Candida kruseiATCC6258,Candida lusitaniae ATCC42720,Candida tropicalis ATCC13803,Cryptococcus gattiiR265,Cryptococcus gattii WM276,Cryptococcus neoformansJEC21,Cryptococcus neoformans ATCC36556,Cryptococcus neoformansvar.grubii H99,Aspergillus fumigatusATCC16424, andTrichophyton mentagrophytes ATCC9533 [6].The effect of new cananginones H-I (154-155) on fungalC. albicanshas been shown to be associated with the IC50 values of 75.2 μM and 37.4 μM, respectively, but new acetogenins cananginones A-G (147-153) did not appear active [40]. Herein, the reason is opposite to antimalarial analysis when four structures151-152 and154-155 were considerably compared.The global health problem in developing countries is becoming increasingly involved in growing and expanding of microbacteria. Historical records have accumulated evidence showing that the use of traditional antibiotics, which are derived from synthetic substances, is always accompanied by a long duration of treatment, high cost, and drug resistance [48]. Therefore, calls for new antibiotic drugs from natural sources in the fight against multidrug-resistant bacteria are always strategy.In a short communication, various components fromM. tomentosa species suppressed the growth of several kinds of bacteria and fungi, but the most significant finding is that leaf volatile oil extract reduced the growth of bacteriumBacillus subtilisNCIM 2250 and fungalC. albicans NCIM 3471 with the same MIC value of 0.62 mg/mL, being better than those of leaf aqueous extract (2.5 mg/mL and 5.0 mg/mL, respectively) [49].Acetogenin A (145) and goniothalamusin (158) are associated with the moderate antibacterial activity with diameters of the inhibitory zone of 9-14 mm against positive Gram bacteriaBacillus cereus,Staphylococcus aureus, andStreptococcusβ-haemolyticusand 9-11 nm against negative Gram bacteriaSalmonella typhi,Shigella flexneri, andShigella dysenteriae, whereas acetogenin A (146) only influencedB. cereuswith diameter zone of 11 mm [5].The MIC values ranged from 32.0 to 64.0μg/mL, which were the moderate antibacterial result of two geranylated homogentisic acids,33 and35, repellent positive Gram bacteriaB. cereus DMST 5040,S. aureus DMST 8013, and methicillin resistantS. aureus. Meanwhile, two other geranylated homogentisic acids,34and36, and two styryls,171 and175, were only found to be associated with the MIC values of 64.0-128.0 μg/mL againstB. cereus DMST 5040 [32]. It was, therefore, concluded that geranylated homogentisic acids seemed to be better candidates for this problem rather than styryl derivatives.At the same time, compound33 revealed the MIC value of 50 μg/mL to treatMycobacterium tuberculosis H37Ra compared with that of the similar structures34-39 (MIC > 50 μg/mL) [32]. Apparently, substituting groups R1 and R2 demonstrated the great role affecting the results.Two unique bicyclic lactones,161-162, resisted the growth ofM. tuberculosis with the MIC values of 43.4 μM and 82.1 μM, respectively, but analogs163-168 showed no activity. It is possible to note that epoxidation and hydroxylation would not be good circumstances to have positive signals in the activity [38].


## 4.5. Anti-Inflammatory Activity

Inflammation can be seen as a part of the complex biological response of the body tissues to harmful stimuli, such as irradiation, physical damage, metabolic overload, or infection [20]. Nowadays, modern diseases, for instance, cardiovascular and neurodegenerative disorders, are closely related to inflammation. Suppressing NO production is recognized to be a useful strategy for this problem.On the screening of anti-inflammatory activity, by using mode of lipopolysaccharides (LPS) (1.0μg/mL)-induced NO production in microglial RAW 264.7 cells, megastigmane glycosides milbasides A-C (179-181), alcohols β-D-glucopyranoside (Z)-3-hexenol (205), and (L)-guaiacyl glycerol 2′-O-β-D-glucopyranoside (208), at a concentration of 20.0 μM, together with flavan (−)-epicatechin (116) and megastigmane glucoside myrsinionoside D (184), at a concentration of 40.0 μM, indicated potent inhibitory activity comparable with or better than positive control sulfuretin (81.3 ± 4.9% at 20.0 μM) [11].Because of glycosylation, NO inhibitory capacity compound208 was generated 2.0-2.5 times higher than those oferythro- andthreo-guaiacylglycerol (206-207) (48.4 ± 3.9%) [11].


## 4.6. Antiherpetic Activity

At the dose of 100μg/mL, methanol extracts from stem and leaf ofM. fragrans showed the IC50 values of 60-80 μg/mL in the antiherpetic experiment against HSV-1 and HSV-2. Meanwhile, in contrast to the inactive results of116-118,120-121,124,128-130,135,139, and143-144, (+)-4-O-demethyleusiderin C (125) and licarin A (131) were found to possess the same IC50 values of 62.5-66.7 μg/mL (HSV-1) and 87.5 μg/mL (HSV-2) [9]. It was figured out that 7S,8R-7.O.3′,8.O.4′-neolignans should be the best choice for this model. Furthermore, by comparing124-125 and129-130, their antiherpetic outcomes closely depended on two functional groups, R1 and R2 (Figure 4).


## 4.7. Antioxidant Activity

Although phytochemical investigation ofM. wayanadica species has not yet been performed extensively, its ethanol leaf extract was observed to be equivalent to or better than positive controls in antioxidant assays. For instance, in DPPH assay, the IC50 value of 465 μg/mL arising fromM. wayanadica ethanol leaf extract was comparable with those of standard compounds BHT (570 μg/mL) and BHA (615 μg/mL); with regard to the ferric reducing antioxidant examination, the IC50 values for these three objects reached 600 μg/mL, 835 μg/mL, and 870 μg/mL, respectively [50].


## 4.8. Enzyme Acetylcholine Inhibitory Activity

To date, only one research dealt with the use of chemical constituents fromM. thorelii species exploring the potency ofMiliusa secondary metabolites in acetylcholinesterase inhibitory activity. The results pointed out that alkaloids (the inhibitory capacity of new oxo-protoberberines23-24 and known one28 reached the significant range of 27.93%-50.17%) were promising agents rather than flavonoids (the inhibitory percentages of <10%-38.68% were for80-83,85-86,88-91,93,95-99, and101-102) or amides (tested compounds201 and203 were inactive, <10%) [32].


## 4.9. Cardiac Activity

Chrysosplenol C (77), a flavonol, isolated fromM. balansae, proved to be an essential backbone to induce a positive inotropic effect on rat ventricular myocytes [12]. This compound caused the contractive percentage of ventricular cell and the active percentage of cardiac myosin ATPase up to 53.0 ± 4.07% at 50 μM and 28.1 ± 1.20% at 10 μM, respectively, compared with those of positive control omecamtiv mecarbil [59.3 ± 2.60% at 400 nM and 80.4 ± 2.89% at 10 μM, respectively] [12].


## 5. Conclusion

Taken together,Miliusaspecies have been fully researched in both phytochemical and pharmaceutical aspects, and a general view of the previous results has been outlined in the current paper. This review mostly focused on the knowledge about botanical description, phytochemistry, and biological evaluation. Basic findings might be concluded as below:(i)
Miliusaplants are widely distributed in tropical and subtropical regions, particularly Asia mainland.(ii)
Based on morphological analysis and the heavy support of DNA-barcoding techniques, the number of newMiliusaplants discovered increased more often. Up to present, approximately sixty species were identified.(iii)
More than tenMiliusa species were highlighted in studying phytochemical and pharmacological aspects. Among them,Miliusa plants, collected from Vietnam, Thailand, and China, were major objectives for phytochemical investigations.(iv)
A variety of secondary metabolites have been successfully isolated. In the current paper, we draw a list of twenty-two hundred isolated compounds. Chemical constituents derived fromMiliusa have fallen into multiple classes of compounds, such as alkaloids, flavonoids, terpenoids, styryls, and lactones, but serial novel derivatives of geranylated homogentisic acid could be seen as biomarkers to recognizeMiliusaspecies.(v)
The geographic factors, environment, and collection time can be responsible for the difference in chemical components of each country. For instance, ThaiM. mollis and M. fragransplants established the high amount of lignans and neolignans whereas some VietnameseMiliusa plants were characterized by the rich flavonoids, terpenoids, or miliusanes.(vi)
Naturally occurring isolated compounds and plant extracts of this genus have been subjected to various pharmacological types, but cytotoxic assay seemed to be the main content of previous researches.(vii)
It was also observed that the biological activation or inactivation of tested compounds closely depended on the key role of functional groups in the chemical structures.(viii)
β-caryophyllene (10%-20%) was considered as major component in essential oils extracted from Vietnamese and AustralianMiliusa plants.Finally, plant growing proposals, scientific assessments, and extensive phytochemical discoveries on this valuable source ought to be a willingness for drug leads and future pharmaceuticals. Bioactive compounds,in vitro andin vivo pharmaceutical analyses, clinical applications, and unknown mechanism explanations are expected.



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*Source: 8314693-2019-08-14.xml*