Anti-Tumor Secondary Metabolites Originating from Fungi in the South China Sea’s Mangrove Ecosystem

A mangrove is a unique ecosystem with abundant resources, in which fungi are an indispensable microbial part. Numerous mangrove fungi-derived secondary metabolites are considerable sources of novel bioactive substances, such as polyketides, terpenoids, alkaloids, peptides, etc., which arouse people’s interest in the search for potential natural anti-tumor drugs. This review includes a total of 44 research publications that described 110 secondary metabolites that were all shown to be anti-tumor from 39 mangrove fungal strains belonging to 18 genera that were acquired from the South China Sea between 2016 and 2022. To identify more potential medications for clinical tumor therapy, their sources, unique structures, and cytotoxicity qualities were compiled. This review could serve as a crucial resource for the research status of mangrove fungal-derived natural products deserving of further development.


Introduction
A mangrove is a unique ecosystem distributed along the coastline of the tropical and subtropical regions, whose specific saline environment is what gives rise to its diverse microbial population [1]. Additionally, the biodiversity of fungi is more abundant than that of other mangrove microorganisms, which has a fairly good prospect of exploration that causes overwhelming focus [2,3]. Modern research suggests that the secondary metabolites which mangrove-derived fungi yielded are considerable sources of novel bioactive compounds [4]. The OSMAC strategy (one strain, many compounds) and co-cultures of mangrove fungus, as well as other microbes, have become the traditional methods for inducing the formation of metabolites [4,5]. The recent explosive multiomics methods wrestle with multi-trophic interactions and computational approaches based on artificial intelligence to estimate function distribution and demonstrate a paradigm change in the use of high-throughput methods for the discovery of natural products from plant-associated microorganisms or traditional Chinese medicine as the potential biomarkers for anti-cancer therapies [6,7]. Further research for these metabolites can be expected to discover their various biological features, such as enzyme inhibition, antimicrobial activity, antitumor activity, anti-inflammatory activity, antiviral activity, cytotoxicity, antioxidant activity, etc. Around the world, mangrove fungus-derived chemicals are being discovered at a progressively higher rate. Among them, many promising ones are beneficial in treating diseases [8].

Sources, Structures, and Anti-Tumor Activities of Secondary Metabolites Originating from Fungal Strains in the Mangrove Ecosystem
One hundred and ten anti-tumor compounds obtained from fungi produced from the South China Sea's mangrove ecosystem were reported from 2016 to 2022 and their classifications, sources, and cytotoxicities (described with IC 50 , the half maximal inhibitory concentration) were listed (Table 1).

Polyketides
Polyketides make up more than half of the recently discovered anti-tumor secondary metabolites of mangrove-associated fungus from 2016 to 2022. They can be branched out into nine categories on the ground of the polyketide backbone, including azaphilones, coumarins and isocoumarins, chromones, lactones, benzoates, xanthones, quinones and benzophenones, phenols, phenyl aldehydes, and phenolic acids, as well as depsidones (Compounds 1-56, Figures 2 and 3).

Azaphilones
Azaphilones, the major class of fungal polyketides, are known to possess the structural features of a highly oxidized pyranoquinone core [61]. In the past seven years, three azaphilones (1-3) with remarkable anti-tumor bioactivity were reported from the fungal genera Diaporthe sp. SCSIO 41011. They originated from the mangrove and were found to possess the specific structure and exhibit inhibition against ACHN, OS-RC-2, and 786-O human renal cancer cell lines (IC 50 values from 3.0 to 38 µM) [17]. Further study showed that the new compound isochromophilone D (1) could induce cell cycle arrest and even apoptosis in 786-O cells. Bioengineering 2022, 9, x FOR PEER REVIEW 12 of 23

Terpenoids
Fungi constitute a class of organisms that are particularly appealing for the discovery of terpenoid pathways because they frequently combine their biosynthetic genes [66]. The new terpenoids, including steroids from mangrove fungi in the South China Sea, can be divided into three categories based on their chemical structures and biogenetic pathways: sesquiterpenes, diterpenes, and steroids (Compounds 57-70, Figure 4).

Steroids
The most significant class of tiny biomolecules, steroids play a variety of cellular functions connected to membrane structure and signaling. Pseudofusicoccum sp. J003 yielded a steroid derivative, ergosterol (70), displaying significant inhibition effects on

Sesquiterpenes
Sesquiterpenes are the largest group and an excellent source of terpenoids, having a high potential for inhibiting various cancers. A group of well-known natural sesquiterpenoids named eudesmanolides has diverse bioactivities [67]. Two eudesmanolides, 13-

Steroids
The most significant class of tiny biomolecules, steroids play a variety of cellular functions connected to membrane structure and signaling. Pseudofusicoccum sp. J003 yielded a steroid derivative, ergosterol (70), displaying significant inhibition effects on HL-60 and SW480 (human colon adenocarcinoma) cells for inhibition rates of 98.68 ± 0.97% and 60.40 ± 4.51% at the concentration of 40 µM [47].

Alkaloids
Alkaloids are a class of compounds containing organic nitrogenous bases that occupy a major part of the secondary metabolites of mangrove fungi. They have been found to have various biological activities [69]. The new alkaloids from mangrove fungi in the South China Sea can be divided into three categories: amines and amides, diketopiperazines, and cytochalasins (Compounds 71-109, Figures 5 and 6).

Alkaloids
Alkaloids are a class of compounds containing organic nitrogenous bases that occupy a major part of the secondary metabolites of mangrove fungi. They have been found to have various biological activities [69]. The new alkaloids from mangrove fungi in the South China Sea can be divided into three categories: amines and amides, diketopiperazines, and cytochalasins (Compounds 71-109, Figures 5 and 6).

Peptides
In many clinical medication treatments, peptides with molecular weights under 1000 Da can adapt to drug resistance and have fewer hazardous side effects, which may have implications for the ongoing development of novel therapies [72]. In the past seven years, only one cyclic peptide was reported to be an anti-tumor peptide (Compound 110, Figure  6).

Discussion
Without a doubt, more and more mangrove secondary metabolites are being discovered and that may be a major source for the creation of novel anti-cancer drugs that can be applied both therapeutically and preventively. Vinca alkaloids are the most notable representatives of plant-derived natural compounds as anticancer weapons, which are frequently utilized as first-line anticancer medications in hematological malignancies [73]. Furthermore, a number of marine isolated targeted compounds, such as Brentuximab2 vedotin (AdcetrisTM), Enfortumab vedotin, and Marizomib, had been used as apoptotic inducers in different cancer types at FDA (the Food and Drug Administration in the US)approved or treatment phases [74]. More effective natural anti-tumor drugs are expected to emerge.
This review concentrated on one hundred and ten anti-tumor secondary metabolites from thirty-nine mangrove fungus strains belonging to eighteen genera from the South China Sea that have been newly reported over the last seven years. Penicillium (23%), Aspergillus (23%), and Lasiodiplodia (11%) were their main producers and at the structural

Peptides
In many clinical medication treatments, peptides with molecular weights under 1000 Da can adapt to drug resistance and have fewer hazardous side effects, which may have implications for the ongoing development of novel therapies [72]. In the past seven years, only one cyclic peptide was reported to be an anti-tumor peptide (Compound 110, Figure 6).

Discussion
Without a doubt, more and more mangrove secondary metabolites are being discovered and that may be a major source for the creation of novel anti-cancer drugs that can be applied both therapeutically and preventively. Vinca alkaloids are the most notable representatives of plant-derived natural compounds as anticancer weapons, which are frequently utilized as first-line anticancer medications in hematological malignancies [73]. Furthermore, a number of marine isolated targeted compounds, such as Brentuximab2 vedotin (AdcetrisTM), Enfortumab vedotin, and Marizomib, had been used as apoptotic inducers in different cancer types at FDA (the Food and Drug Administration in the US)-approved or treatment phases [74]. More effective natural anti-tumor drugs are expected to emerge.
This review concentrated on one hundred and ten anti-tumor secondary metabolites from thirty-nine mangrove fungus strains belonging to eighteen genera from the South China Sea that have been newly reported over the last seven years. Penicillium (23%), Aspergillus (23%), and Lasiodiplodia (11%) were their main producers and at the structural level, polyketides occupy more than half of the secondary metabolites. Seventy-eight compounds were considered to possess multiple anti-tumor properties, as they exhibited cytotoxicity against more than two tumor cell lines.
It has been proposed that mangrove fungal-derived drugs could be effective weapons for human beings to fight cancer. However, the potential regulatory mechanisms of the vast anti-tumor compounds on tumor microenvironment still need to do in-depth exploration. The bulk of them could not be employed temporarily in tumor diagnosis and treatment due to the lack of reliable clinical research data and studies confirming their biosafety. Additionally, a fungal culture is restricted by special environments or growth factors. Co-cultures of fungi are a popular way to promote the production of metabolites, such as nafuredin B (12), botryorhodine H (55), and botryorhodine C (56), and in the future, multi-omics methods will be richer than the secondary metabolites of mangrove-derived fungi and will be good for screening anti-cancer compounds. Another challenge is figuring out how to produce these secondary metabolites in large quantities.
To date, chemotherapy remains to be regarded as the cornerstone of many adjunctive therapies for cancer. Recently, the design and development of efficient anti-cancer treatment strategies have advanced, and decisions regarding treatment have taken the immunological perspective of chemotherapy into account. Because nucleotides are significant chemicals that must be generated to sustain the state of proliferation in cancer, nucleotide metabolism is regarded as the most crucial link in oncogenesis and progression [75]. On the one hand, targeted regulation of the level of nucleotide metabolism can make tumor cells more sensitive to chemotherapy drugs, mediate anti-tumor response, and enhance the efficacy of chemotherapy and immunotherapy in the treatment of tumors [75,76]. A good anti-tumor impact may also be obtained by altering the amount of nucleotide metabolism, such as by providing exogenous UDP (uridine diphosphate) to modify the tumor microenvironment [77]. This makes immunotherapy tend to have a similar outcome to chemotherapy. On the other hand, chemotherapy stimulates the immune system and triggers tumor cells to undergo immunogenic cell death (ICD) [78]. An important feature of ICD is the extracellular release of ATP from dying cells after apoptosis. For example, daunorubicin, a classic anthracycline anti-tumor drug, induced ATP release into the extracellular space of acute myeloid leukemia cells and was considered a very strong ICD inducer [79]. Another possible drug from the Agelas mauritianus sponge, KRN7000, was found to play an anti-tumor role by activating the immune system, having been put into a clinical investigation for many years [80]. In addition, the level of nucleotide release will also be one of the indicators to evaluate the efficacy of anti-tumor drugs in the near future [81].

Conclusions
Looking forward to the newly developed anti-cancer treatment strategies and anticancer metabolite discovery strategies, this review serves as a crucial resource for the research status of mangrove fungal-derived natural products deserving of further development, demonstrating the great medical benefits of mangrove fungal-derived drugs for the treatment of clinical cancers.

Data Availability Statement:
No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest:
The authors declare no conflict of interest.