*3.1. Polyketides*

Polyketides are a class of secondary metabolites that are produced by bacteria, fungi, actinobacteria, and plants [48,49]. They include polyphenols, macrolides, polyenes, anthraquinones, enediynes, and other compounds [50,51]. Polyketides have diverse bioactive properties, including antibiotic, antifungal, immunosuppressant, antiparasitic, cholesterollowering, and antitumoral activities [50,52].

The polyketones territrem A (**1**), territrem B (**2**), dihydrogeodin (**3**), emodin (**4**), questin (**5**), and 1-(2,4-dihydroxyphenyl)-ethanone (**6**) were isolated from the marine fungus *Aspergillus terreus*, associated with the sea cucumber *A. japonicus*, collected from Zhifu Island in Yantai, China [39]. Compounds **4** and **5** are common quinone compounds, and compound **4** has cytotoxic effects on human oral epithelial cancer cells (KB) and multidrug-resistant cells (KBv200), with IC50 values of 32.97 and 16.15 μg/mL, respectively [39]. Compound **4** was also isolated from sea-cucumber-derived fungus *Trichoderma* sp., and it showed weak

inhibitory effects against *Pseudomonas putida*, with a minimum inhibitory concentration (MIC) of 25 μM [44]. Compound **5** has weak cytotoxicity in KB and KBv200 cells, with IC50 values > 50 μg/mL [39].

Three additional compounds, 1-hydroxyl-3-methylanthracene-9,10-dione (**7**), chrysophanol (**8**), and sterigmatocystin (**9**), are secondary metabolites of the fungus *Alternaria* sp., isolated from sea cucumber in the sea surrounding Zhifu Island in Yantai, China [28]. Compound **8** was also isolated from a sea-cucumber-associated fungus *Trichoderma* sp. and showed weak inhibitory effects against *Vibrio parahaemolyticus*, with an MIC value of 25 μM [44].

The anthraquinone compounds coniothyrinone A (**10**) and lentisone (**11**) were isolated from the fungus *Trichoderma* sp. associated with a sea cucumber that was collected from Chengshantou Island in the Yellow Sea in Weihai City, China [44]. Compounds **10** and **11** were isolated for the first time from fungi of the genus *Trichoderma*, and they had weak antiangiogenicc activity. Compound **10** showed pronounced antibacterial activity against three common marine pathogens, *Vibrio parahaemolyticus*, *Vibrio anguillarum*, and *Pseudomonas putida*, and the MIC values were 6.25, 1.56, and 3.13 μM, respectively. Compound **11** showed inhibitory effect against *V. parahaemolyticus*, *V. anguillarum*, and *P. putida*, with MIC values of 12.5, 1.56, and 6.25 μM, respectively [44].

Six compounds, javanicin (**12**), norjavanicin (**13**), fusarubin (**14**), terrain (**15**), sclerin (**16**), and 5-hydroxy-7-methoxy-3-methyl-2-(2-oxopropyl) naphthalene-1,4-dione (**17**), were isolated from the sea-cucumber-associated fungus *Fusarium* sp. from the Yantai Sea, China [45]. Compounds **12**–**14** showed moderate cytotoxicity in KB cells, with IC50 values of 2.90, 10.6, and 9.61 g/mL, respectively, and they also showed moderate cytotoxic effects in KBv200 cells, with IC50 values of 5.91, 12.12, and 6.74 g/mL, respectively [45].

Four new polyhydroxy cyclohexanol analogues, named dendrodochol A–D (**18**–**21**), were isolated from the fungus *Dendrodochium* sp. associated with the sea cucumber *H*. *nobilis*, which was collected from the South China Sea [53]. Compounds **18** and **20** showed modest antifungal activity against *Candida* strains, *Cryptococcus neoformans*, and *Trichophyton rubrum* (MIC80 = 8–16 μg/mL) in an in vitro bioassay [53]. Additionally, thirteen new 12-membered macrolides, dendrodolides A–M (**22**–**34**), were isolated from the fungus *Dendrodochium* sp. associated with the sea cucumber *H*. *nobilis* [37]. Compounds **22**–**25**, **29**, **30**, and **32** showed cytotoxic effects on SMMC-7721 tumor cells, with IC50 values of 19.2, 24.8, 18.0, 15.5, 21.8, 14.7, and 21.1 μg/mL, respectively [37]. Compounds **24**, **26**, **28**, **30**, **32**, and **33** had cytotoxic effects on HCT116 tumor cells, with IC50 values of 13.8, 5.7, 9.8, 11.4, 15.9, and 26.5 μg/mL, respectively [37].

Aspergillolide (**35**), a newly discovered 12-membered macrolide, was isolated from the fungus *Aspergillus* sp. S-3-75, associated with the sea cucumber *H*. *nobilis* that was collected from the Antarctic [35].

Azaphilone compounds are fungal polyketide pigments produced by a variety of ascomycetes and basidiomycetes [54]. Four previously known azaphilones, chaetoviridin A (**36**), chaetoviridin E (**37**), chaetoviridin B (**38**), and chaetomugilin A (**39**), and a known cochliodinol (**40**), were produced by the fungus *Chaetomium globosum*, associated with the sea cucumber *A. japonicus*, which was collected from Chengshantou Island, Weihai, China [29].
