*2.6. Polyketides*

Twelve polyketides were isolated and characterized from the marine microbial co-cultures in recent years (Figures 2B and 21).

**Figure 21.** Polyketides isolated from the co-culture of marine fungi–fungi, fungi–bacteria and bacteria–bacteria.

#### 2.6.1. Polyketides Derived from the Co-Cultures of Different Marine Fungi

In 2014, Ebada et al. identified three previously reported polyketide derivatives, sterigmatocystin (**124**), 5-methoxysterigmatocystin (**125**) and aversin (**126**) (Figure 22) from the ethyl acetate extract of two marine alga-derived fungi, *Aspergillus* sp. BM-05 and BM-05ML [30]. Kossuga et al. isolated two new and unusual polyketides: (*Z*)-2-ethylhex-2-enedioic acid (**127**) and (*E*)-4-oxo-2-propylideneoct-7-enoic acid (**128**) (Figure 22) from the marine-derived fungi *Penicillium* sp. Ma(M3)V isolated from the marine sponge *Mycale angulosa* co-cultivated with *Trichoderma* sp. Gc(M2)1 isolated from the marine sponge *Geodia corticostylifera* [76]. Two unprecedented polyketides (**127**–**128**) had a common feature—a conjugated carboxylic acid group that could be biogenetically generated from the methyl group of an acetate rather than a methionine precursor in **127**, and the same group could be derived from C-1 position of an acetate or C-2 position of a propionate in **128** based on the precursor of the ethyl group connected to a double bond. It was an excellent case of a truly novel carbon skeleton induced by the powerful and underexplored method, marine microbial co-cultivation.

**Figure 22.** Chemical structures of **124**–**128**.

Compound **124** showed in vitro anti-proliferative activities towards human cisplatin-resistant ovarian cancer A2780CisR, ovarian cancer A2780 and chronic myelogenous leukemia K562 cell lines with IC50 values of 95.5, 30.6 and 57.0 μM, respectively. Moreover, it also displayed more significant anti-proliferative activities against human colon carcinoma HCT116 cells with an IC50 value of 10.3 μM (cf. to cisplatin's IC50 33.4 μM). Compound **125** exhibited potent in vitro anti-proliferative activities towards three human cancer cell lines, HCT116, A2780 and human chronic myelogenous leukemia (K562) with IC50 values of 4.4, 51.0 and 13.4 μM, respectively [30].

2.6.2. Polyketides Derived from the Co-Cultures of Marine Fungi and Bacteria

A pair of enantiomers (9*R*,14*S*)-epoxy-11-deoxyfunicone (**129**) and (9*S*,14*R*)-epoxy-11- deoxyfunicone (**130**), along with deoxyfunicone (**131**), alternariol (**132**) and vermistatin (**133**) (Figure 23) were isolated from the co-culture of *Penicillium* sp. WC-29-5 isolated from the mangrove soil around the roots of *Aegiceras corniculatum* and *Streptomyces fradiae* 007 isolated from a sediment sample in the Jiaozhou Bay, Shandong Province, China [77].

**Figure 23.** Chemical structures of **129**–**133**.

Both **129** and **130** exhibited moderate inhibitory activity against H1975 tumor cell lines with IC50 values of 3.97 and 5.73 μM, respectively. Deoxyfunicone (**131**) was found to exert anti-inflammatory activity, exhibiting the inhibition effect on overproduction of nitric oxide (NO) and the prostaglandin E2 in both lipopolysaccharide-provoked BV2 microglial and lipopolysaccharide-stimulated RAW264.7 macrophage cells (IC50 = 10.6 and 40.1 μM, respectively) [78]. **132** was known as a cytotoxic, genotoxic, mutagenic and fetotoxic mycotoxin [79,80]. However, in the IL-1β-stimulated Caco-2 cells, the metabolite **132** increased the transcription of TNF-α; inversely reduced the transcription of IL-1β and IL-6; and decreased the transcription and secretion of IL-8, suggesting that **132** possessed immunomodulatory activities on both lipopolysaccharide- and IL-1 β-related pathways in non-immune intestinal epithelial cells [79].

#### 2.6.3. Polyketides Derived from the Co-Cultures of Different Marine Bacteria

Recently, two unusual polyketides, janthinopolyenemycins A (**134**) and B (**135**) (Figure 24) were purified and identified from the co-cultivation broth of two marine bacteria *Janthino bacterium* spp. ZZ145 and ZZ148 isolated from marine soil sample [81]. Both **134** and **135** displayed the same antifungal activity against *C. albicans* with a minimum bactericidal concentration (MBC) value of 31.25 μg/mL and an MIC value of 15.6 μg/mL. However, none of them could suppress the growth of methicillin-resistant *S. aureus* or *E. coli* (MIC > 100 μg/mL) [81].

**Figure 24.** Chemical structures of **134**–**135**.
