# Naphthoquinone-Based Meroterpenoids from Marine-Derived _Streptomyces_ sp. B9173
## 1 Introduction  
Marine-derived microbial natural products are great sources for the discovery and development of pharmaceutical agents [1; 2; 3]. Marine Streptomyces continue to be the predominant producers, accounting for up to 69% of new secondary metabolites isolated from marine bacteria in 2018 [4]. Meanwhile, the genome of each Actinomycetes indicates genetic potential to produce 20-30 secondary metabolites. The rapidly accumulating microbial genomic information and developing bioinformatics platforms are further stimulating the revolution for natural product discovery [5]. However, the biosynthetic potential of microbial natural products is significantly underestimated based on the isolated compounds. It is hampered by the laboratorial cultivation methods, since many of these \"cryptic\" gene clusters are only expressed under certain culture conditions. Additionally, metabolite production is strongly influenced by growth conditions, including production media, pH, temperature, etc. [6; 7].  
Naphthoquinone-based terpenids are natural products of mixed biosynthetic origin and exhibit antimicrobial, cytotoxic, antioxidant, and neuroprotective activity [8]. Examples include flavioregranin, furaquinocin, nabterpin, naphthalene, and merochlorins, etc. [9] (Figure 1). Flaviogeranin is a neuroprotective agent against glutamate toxicity and is becoming a candidate for treatmentof cerebral ischemic disorder [10]. Furaquinocins show cytocidal activity against melanoma cells in vitro [11]. These naphthoquinone-based meroterpenoids contain a 1,3,6,8-tetrahydrooxynaphthalene (THN) core formed by a type III polykeletid synthase (PKS) using malonyl-CoA as a substrate [12; 13; 14; 15; 16]. The preryl moieties are suggested to play important roles in expanding structural diversity and enhancing biological activities. Simple preryl groups are derived from geranyl diphosphate (GPP) or dimethylallyl diphosphate (DMAPP), and geranylgeranyl diphosphate gives rise to diterpenoids. Preryltransferases catalyze the attachment of the corresponding polyprenyl group to the THN core [17]. The C3 of THN is not as nucleophilic as C2 and C4. Therefore, THN-derived meroterpenoids can be divided into C2/C4- prenylation (class I) and C3 prenylation pattern (class II). Successive steps such as methylation, hydroxylation, and chlorination are catalyzed by multiple modifying enzymes during the biosynthetic procedure, further enriching the structural diversity of the final products.  
Our natural products project is devoted to the discovery of new bioactive metabolites from marine-derived actinomycetes. _Streptomyces_ sp. B9173 was isolated from sea sediment collected from Chile. By optimization of growth conditions of _Streptomyces_ sp. B9173, several indole alkaloids, such as maremycins, FR900452s, tryptanthrin, and meiosisindigo, have been identified [18; 19; 20; 21]. An in-depth bioinformatic investigation of secondary biosynthetic machineries of the whole genome yielded 31 gene clusters, clearly implying the biosynthetic potential of this strain [22]. Here, we report the isolation and structure determination of a group of flaviogeranin derivatives and pathway intermediates from _Streptomyces_ sp. B9173 (Figure 2). Three previously undescribed compounds (**1-3**) with different oxidations, methylation, or prenylation on the THN core show unique characteristics compared with the known flaviogeranin. Among them, **1** and **2** are the only members containing an amino group at the C8 of THN instead of the hydroxyl group. These features expand the structural diversity of the flaviogeranin family of natural products, and these compounds provide evidence of the biosynthetic pathway. The new compound **3** showed potent antibacterial and cytotoxic activity.  
Figure 1: Representative naphthoquinone-based meroterpenoids.  
Figure 2: Structures of flaviogeranin congeners isolated from _Streptomyces_ sp. **1–3** are new compounds and **4–7** are known compounds.