# Guineensine: Isolation, Synthesis, and Biological Activity
## 1 Introduction
### Guinensine and Structural Classification of Fatty Acid-Derived Piperamides  
Guinenesulf (2\(E\), 4\(E\), 12_E_)-13-(benzo [_d_][1,3]dioxol-5-yl)-\(N\)-isobutyltrideca-2,4,12-trienamide) **1** was first isolated in 1974 by [PERSON] et al. from fruits of _P. guinenes_, collected in the western parts of Nigeria [22]. Its chemical structure was elucidated by [PERSON] et al. and found to contain three distinct units (Figure 1) [23]: a terminal benzodioxolyl group (from this point called as tail group), a terminal isobutylamide group (from now on called as head group), and a fatty acid-derived linker. The latter is an unsaturated twelve-carbon chain connecting the aforementioned terminal groups. No _cis-trans_ isomeric forms of guinensine were isolated from _Piper_ species [24]. Guineainse is a bioactive member of the piperamides family. The amide alkaloids found in _Piper_ species are commonly known as piperamides [25]. Among them, piperine is the most abundant pungent alkaline and is widely studied for its biological properties [26; 27]. On the other hand, guineainse belongs to a special family  
Figure 1: The structure of guinensine **1**, divided in three core parts (**up**) and the structure of the most common piperamide; piperine (**down**). of fatty acid (FA)-derived piperamides sharing common structural features, along with differences with piperine (Figure 1). Apart from the obviously similar skeleton, they are both characterized by a benzodioxolyl terminal group. However, guineainse has a more complex unsaturated carbon chain with isolated double carbon bonds and an isobutyl group attached to the amidic nitrogen, instead of the conjugated carbon chain and the piperidine terminal moiety of the piperine. The FA piperamide family, structurally analogue to guineainse **1**, includes retrotrans A **2**[28], B **3** (known also as pipercle) [29], C **4**[28] and D **5**[30], brachystamides B **6**[31] and D **7**[30], and piperchabamide D **8**[32] and pipgulzarine **9**[33] (Figure 2). Products **1-9** have a styryl double bond attached to the aryl group. Broadly similar to the previous products are dihydropypercide **10**[34], chingchengamide A **11**[35], dihydropyperlonguminine **12**[36], pipercallosine **13**[37], and brachystamide A **14**[31] (Figure 3). These products lack the double bond adjacent to the tail aromatic group. A number of isolated piperamides incorporate a methylene group between the benzodioxolyl group and the isolated C=C. Laetispicine **15**[38], ridleyamide **16**[39], and brachystamide C **17**[27] belong to this subgroup of FA piperamides (Figure 4). Figure 3: FA–piperamides lacking the carbon–carbon double bond next to benzodioxolyl group. Figure 2: FA–piperamides structurally analogues to guineainse. Products mentioned in this list contain one or more isolated double bonds separated by one or more saturated carbon atoms. However, it is worth noting that the natural products, fagaramide **18**[40] and piperlonguminine **19**[41], with a conjugated chain of one or two double bonds, respectively, are closer to the structure of piperie (Figure 5). Although the FA piperamide family is dominated by all-\(E\) carbon double bonds, the natural products piperlongummide E **20**[40] and (3Z, 5Z)-\(N\)-isobutyl-8-(3\({}^{\prime}\)A\({}^{\prime}\)-methylenedioxypphenyl)-heptadienamide **21**[42] contain one or more C=C with \(Z\) configuration (Figure 6). The above list is limited to natural products isolated from _Piper_ species. More piperamides obtained by organic synthesis exist and some of them will be discussed later. Guineensine was isolated originally from _P. guiweense_ from which it owes its name [22]. However, it is present in the dietary pepper species _P. nigrum_[43] and _P. longum_[44], used also in traditional medicine, as well as in the lesser-known _P. submultinerev_[45], _P. attenutum_[46], _P. brachystachyum_[44], _P. hanci_[46], _P. retrofract_[47], and others. As with  
Figure 4: FA–piperamides with one or more methylene units next to benzodioxolyl group.