A Review on Bioactive Compounds from Marine-Derived Chaetomium Species

Filamentous marine fungi have proven to be a plentiful source of new natural products. Chaetomium, a widely distributed fungal genus in the marine environment, has gained much interest within the scientific community. In the last 20 years, many potential secondary metabolites have been detected from marine-derived Chaetomium. In this review, we attempt to provide a comprehensive summary of the natural products produced by marine-derived Chaetomium species. A total of 122 secondary metabolites that were described from 2001 to 2021 are covered. The structural diversity of the compounds, along with details of the sources and relevant biological properties are also provided, while the relationships between structures and their bioactivities are discussed. It is our expectation that this review will be of benefit to drug development and innovation.


Introduction
. Natural products isolated from marine-derived Chaetomium species.

Structure
Natural product Species Bioactivity Source Ref.

Cytochalasans
Cytochalasans are a large group of fungal alkaloids with a wide range of biological activities. They have been an important chemical tool in cell and molecular biology. Some of them also possess phytotoxic, cytotoxic, and antibiotic activities [9,10]. Cytochalasans are characterized by a highly substituted perhydro-isoindolone moiety incorporating a macrocyclic ring [11]. The fungal polyketide synthase nonribosomal peptide synthetase (PKS-NRPS) plays an important role in forming cytochalasans [12].

Dioxopiperazines
Dioxopiperazines are common metabolites of microorganisms that are distributed in a diverse range of filamentous fungi [23,24]. Many dioxtopiperazines reported from marine-derived fungi display a variety of pharmacological properties, particularly in the field of antitumor and antimicrobial therapy [25].

Fig. 1. Cytochalasans produced by marine-derived Chaetomium species.
Recently, cristazine (37) was evidenced to have great potential for inducing apoptosis via the death receptor pathway in human epidermoid carcinoma (A431) cells [27]. Chetomin (38) is an antibiotic discovered more than 70 years ago [28]. Recently, it was found to be a potent HIF-1 inhibitor [29] and exhibited antitumor activity in lung cancer, multiple myeloma, and breast cancer [30][31][32]. Neoechinulin A (39) was shown to possess a variety of activities, including anti-inflammatory [33], SARS-CoV-2 M pro inhibiting [34], cytoprotective [35], memory improvement and antidepressant-like effects [36]. In addition, the structure-activity relationship of neoechinulin A revealed that the presence of a diketopiperazine ring was essential for its antioxidant and anti-nitration activities [37].

Indole Alkaloids
Indole alkaloids are the active moiety of several clinical drugs, such as reserpine, tadalafil and fluvastatin, which are all designed based on an indole skeleton [38,39]. The indole framework is widely distributed in many fungal natural products [40,41]. 19-O-demethylchaetogline A (54) and 20-O-demethylchaetogline F (55), together with two known ones, 42 and 47, were produced. Compound 50 was found to be antibacterial against Xanthomonas oryzae pv. oryzae (xoo), a pathogen causing rice bacterial leaf blight. Compound 42 was shown to be inhibitory against rape pathogenic fungus Sclerotinia sclerotiorum [43].

Azaphilones
Azaphilones are natural products characterized by an oxygenated bicyclic core that bears an oxygenated nonprotonated carbon in position 7, and are widely distributed in fungi [44,45]. Azaphilones exhibit broadspectrum biological activities, including anticancer, antioxidant, anti-inflammatory, antibacterial, antifungal and other activities [46]. Chemical investigation of C. globosum OUPS-T106B-6, which was originally isolated from the marine fish Mugil cephalus, resulted in a series of azaphilones being obtained. The compounds included  [53], and chaetomugilins S-U (79-81) [54] (Fig. 4). All of these were tested for cytotoxicity against human cancer cell lines, and chaetomugilins A, C, F, and I showed significant cytotoxic activity against 39 cell lines, while other chaetomugilins exhibited selective growth inhibition of some cultured cancer cell lines. Particularly, chaetomugilin J inhibited PINK1/Parkin-mediated mitophagy to enhance apoptosis in A2780 cells induced by cisplatin [55].

Conclusion
This review summarized 122 secondary metabolites with potent bioactivities derived from marine environment species, reported from 2001 to 2021, and which will benefit future drug development and innovation. As for the structure types of the compounds, we covered cytochalasans (29.51%), dioxopiperazines (3.28%), indole alkaloids (12.30%), azaphilones (36.89%), xanthone derivatives (4.92%) and others (13.11%), indicating the chemical diversity of marine Chaetomium. The natural products originating from marine-derived Chaetomium species also showed a multiplicity of biological activity, including cytotoxicity, enzyme inhibitory activity, radical-scavenging activity, antiparasitic, antibacterial, and antifungal activity.
It is noteworthy that most of the metabolites were isolated from C. globosum strains. When compared to the large number of species (more than 100) contained in Chaetomium, very few have been screened for the production of interesting secondary metabolites. This situation may be attributed to the difficulty in cultivating marine microorganisms, especially certain deep-sea-derived fungi that cannot survive under normal laboratory conditions and therefore must be cultured using nontraditional techniques [74,75]. As a result, the potential of Chaetomium genus derived from marine Chaetomium remains virtually untapped.