A Review: Halogenated Compounds from Marine Fungi

Marine fungi produce many halogenated metabolites with a variety of structures, from acyclic entities with a simple linear chain to multifaceted polycyclic molecules. Over the past few decades, their pharmaceutical and medical application have been explored and still the door is kept open due to the need of new drugs from relatively underexplored sources. Biological properties of halogenated compounds such as anticancer, antiviral, antibacterial, anti-inflammatory, antifungal, antifouling, and insecticidal activity have been investigated. This review describes the chemical structures and biological activities of 217 halogenated compounds derived mainly from Penicillium and Aspergillus marine fungal strains reported from 1994 to 2019.


Introduction
Marine fungi are a treasure source of marine natural products. Marine-derived fungi are important providers of biologically prominent natural products due to their ability to produce secondary metabolites with novel structures and pharmacological activities. According to a paper on marine microbial natural products from 2010 to 2013 [1], natural products from marine fungi account for 63% of marine microorganisms. Due to the enormous amount of chloride and bromide ions available in seawater, many of these secondary metabolites are halogenated. Marine natural products cover a diverse assembly of molecules, including polyketides, peptides, terpenes, phenols, acetogenins, alkaloids, and volatile halogenated hydrocarbons [2]. The fungi isolated from the marine sources might also be found in the terrestrial region. However, marine derived fungi usually produce more halogenated compounds than their terrestrial counterparts due to the presence of high halogen concentrations in the Ocean. Halogenated natural products encompass many classes of compounds, ranging in complexity from halocarbons (mostly halomethanes and haloethanes) to higher molecular weight molecules, which often contain oxygen and/or nitrogen atoms in addition to halogens [3,4]. One of the major focal points of research undoubtedly has been the discovery and characterization of new halogenated compounds, along with a remarkable effort toward the assessment of their possible pharmacological activities and biomedical applications. Active compounds account for nearly 59.2% new halogenated natural products isolated from marine fungi. This paper provides an overview of the sources of marine-derived fungi, chemical structures, and biological activities of 217 halogenated compounds (Table S1) derived from marine fungi from 1994 to 2019.

Other Marine Animals-Associated Aspergillus sp.
Notoamide N (49) and notoamide P (50) were isolated from the cultures of Aspergillus sp. MF297-2 [28,29]. A mycotoxin ochratoxin A n-butyl ester (51) was isolated from a marine-derived fungal strain Aspergillus sp. SCSGAF0093 from Melitodes squamata collected from the South China Sea. The bio-toxicity of compound 51 was determined by the brine shrimp lethality bioassay with a median lethal concentration (LC 50 ) value of 4.14 µM [30]. Two new indole-diterpene alkaloids asperindoles A (52) and C (53)

Other Marine Sediments-Associated Fungi
Chlorogentisylquinone (185) was purified from a marine-derived fungus FOM-8108, which showed nSMase activity with an IC 50

Conclusions
According to our summary of halogenated compounds identified from 1994 to 2019 ( Figure 6, Table 1), the research on halogenated compounds from marine fungi was traced back to 1994 when chloriolins A-C (74-76) were discovered from an unidentified fungus isolated from the Indo-Pacific sponge Jaspis aff. johnstoni (Table 2) [41]. Since 2008, more new halogenated compounds than ever from marine fungi were isolated annually except before 2016. By the end of 2019, 217 new halogenated compounds from marine fungi have been reported. We have done our best to include as many new halogenated compounds isolated from marine fungi as possible, but the list may still not be complete.

Conclusions
According to our summary of halogenated compounds identified from 1994 to 2019 ( Figure 6, Table 1), the research on halogenated compounds from marine fungi was traced back to 1994 when chloriolins A−C (74−76) were discovered from an unidentified fungus isolated from the Indo-Pacific sponge Jaspis aff. johnstoni (Table 2) [41]. Since 2008, more new halogenated compounds than ever from marine fungi were isolated annually except before 2016. By the end of 2019, 217 new halogenated compounds from marine fungi have been reported. We have done our best to include as many new halogenated compounds isolated from marine fungi as possible, but the list may still not be complete.

214-217
Chaetomium sp. NA-S01-R1 A seawater sample, the West Pacific Ocean antimicrobial activity, cytotoxicity [113] Most of the papers that reported new halogenated compounds in this period of time    Fungi isolated from sponges, sediments, algae, and mangroves produced most of the new halogenated compounds (22.6, 27.6, 11.1, and 10.6%, respectively) ( Figure 9). Marine animals hosted diverse fungal species and strains that produced more than 50% of the new halogenated compounds from 1994 to 2019, indicating that they are an excellent source for the discovery of new halogenated compounds. Fungi isolated from sponges, sediments, algae, and mangroves produced most of the new halogenated compounds (22.6, 27.6, 11.1, and 10.6%, respectively) ( Figure 9). Marine animals hosted diverse fungal species and strains that produced more than 50% of the new halogenated compounds from 1994 to 2019, indicating that they are an excellent source for the discovery of new halogenated compounds. The numbers of halogenated compounds from marine Penicillium sp., Aspergillus sp., and the other fungi were 38, 35, and 144, respectively ( Figure 10). It seems that halogenation in the marine environment is not specifically favorable to any fungal species or strains. Therefore, it would be interesting to investigate whether halogenations in marine fungi are enzymatic or nonenzymatic. The numbers of cytotoxic and antimicrobial halogenated compounds from marine fungi account for 32.6 and 18.9%, respectively ( Figure  11). In addition, 39.2% of the halogenated compounds were tested as inactive in the reported assays, but it is worthy to evaluate these compounds in other biological settings. The numbers of halogenated compounds from marine Penicillium sp., Aspergillus sp., and the other fungi were 38, 35, and 144, respectively ( Figure 10). It seems that halogenation in the marine environment is not specifically favorable to any fungal species or strains. Therefore, it would be interesting to investigate whether halogenations in marine fungi are enzymatic or nonenzymatic. The numbers of cytotoxic and antimicrobial halogenated compounds from marine fungi account for 32.6 and 18.9%, respectively ( Figure 11). In addition, 39.2% of the halogenated compounds were tested as inactive in the reported assays, but it is worthy to evaluate these compounds in other biological settings.
These new marine natural products from marine fungi have different structure skeletons including polyketides, nitrogen-containing compounds, sterols, and terpenoids ( Figure 12). Polyketides account for the majority (169, 78%) of the new halogenated compounds (217) isolated from marine fungi ( Figure 12). The number of chlorinated compounds is 191, which is far more than that of brominated compounds simply due to the fact that chloride/chlorine is dominant in the Ocean when compared with bromide/bromine ( Figure 13). (1994-2019).
The numbers of halogenated compounds from marine Penicillium sp., Aspergillus sp., and the other fungi were 38, 35, and 144, respectively ( Figure 10). It seems that halogenation in the marine environment is not specifically favorable to any fungal species or strains. Therefore, it would be interesting to investigate whether halogenations in marine fungi are enzymatic or nonenzymatic. The numbers of cytotoxic and antimicrobial halogenated compounds from marine fungi account for 32.6 and 18.9%, respectively ( Figure  11). In addition, 39.2% of the halogenated compounds were tested as inactive in the reported assays, but it is worthy to evaluate these compounds in other biological settings.  These new marine natural products from marine fungi have different structure skeletons including polyketides, nitrogen-containing compounds, sterols, and terpenoids ( Figure 12). Polyketides account for the majority (169, 78%) of the new halogenated compounds (217) isolated from marine fungi ( Figure 12). The number of chlorinated compounds is 191, which is far more than that of brominated compounds simply due to the fact that chloride/chlorine is dominant in the Ocean when compared with bromide/bromine ( Figure 13). These new marine natural products from marine fungi have different structure skeletons including polyketides, nitrogen-containing compounds, sterols, and terpenoids ( Figure 12). Polyketides account for the majority (169, 78%) of the new halogenated compounds (217) isolated from marine fungi ( Figure 12). The number of chlorinated compounds is 191, which is far more than that of brominated compounds simply due to the fact that chloride/chlorine is dominant in the Ocean when compared with bromide/bromine ( Figure 13).   One of the challenges of discovering promising biologically active secondary metabolites from marine fungi is to mimic the culture environment as the marine. The surrounding environment such as oxygen, pressure, light, and salinity etc. significantly influence the growth of the marine fungi, as well as their ability to produce secondary metabolites. Although it is a challenge, investigating marine fungi for their halogenated secondary metabolites is worth it since more than 60% halogenated compounds isolated from marine fungi have some kind of significant biological activities. It is also worthy to assess halogenated compounds in a broader range of assays. One of the challenges of discovering promising biologically active secondary metabolites from marine fungi is to mimic the culture environment as the marine. The surrounding environment such as oxygen, pressure, light, and salinity etc. significantly influence the growth of the marine fungi, as well as their ability to produce secondary metabolites. Although it is a challenge, investigating marine fungi for their halogenated secondary metabolites is worth it since more than 60% halogenated compounds isolated from marine fungi have some kind of significant biological activities. It is also worthy to assess halogenated compounds in a broader range of assays.