Novel Natural Products from Extremophilic Fungi

Extremophilic fungi have been found to develop unique defences to survive extremes of pressure, temperature, salinity, desiccation, and pH, leading to the biosynthesis of novel natural products with diverse biological activities. The present review focuses on new extremophilic fungal natural products published from 2005 to 2017, highlighting the chemical structures and their biological potential.

isolated strains were selected strictly according to the above categories and that strains which do not meet the standards were not cited. For example, one strain was isolated from the deep sea but its underwater depth was less than 3000 m, which did not meet the criteria of piezophiles. Therefore, we did not include it in this review.

Psychrophilic Fungi
Psychrophilin D (144) (Figure 24), a new cyclic nitropeptide was isolated from Penicillium algidum derived from a soil sample in Greenland. This compound exhibited moderate cytotoxic activity against P388 murine leukaemia cells with an ID 50 value of 10.1 µg/mL. When evaluated for antimicrobial, antiviral, anticancer and antiplasmodial activities compound 144 proved to be inactive [51]. According to the structure-bioactivity relations, the cyclopropane ring in 148 and 150 appears to be an important structural feature associated with their biological activity [53]. Later Chu's group found that 150 biosynthesis was significantly elevated (16.4 folds) with ethanol treatment, and further study showed that the gene transcription levels of 3-hydroxy-3-methyl glutaric acyl coenzyme A reductase and geranylgeranyl diphosphate synthase were up-regulated by ethanol stimulation [54]. Several new compounds including cytochalasins Z 24 , Z 25 , Z 26 (151-153) ( Figure 25) [55], eutypenoids A-C (154-156) ( Figure 25) [56], and eut-Guaiane sesquiterpene (157) (Figure 25) [57] have been described from the same fungal strain since 2014. Compound 151 exhibited a moderate cytotoxicity against MCF-7 cells with an IC 50 value of 9.33 µM. Compound 155 was able to suppress the proliferation of BALB/c mice splenocytes under ConA induction. Antibacterial activity (Escherichia coli, Bacillus subtilis, and Staphylococcus aureus) of compound 157 was comparable to that of ampicillin but cytotoxic activity against SGC7901 cells was very weak (IC 50        Two different Lindgomycetaceae strains KF970 and LF327 obtained from different marine habitats (Antarctic and the Kiel Fjord, Baltic Sea) both produced lindgomycin (186) (Figure 30), an unusual polyketide with a unique 5-benzylpyrrolidine-2,4-dione unit at the tetramic acid substructure. Antibiotic activity (Bacillus subtilis, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus) of compound 186 were two times less than that of chloramphenicol (the positive control) [64]. The psychrotolerant fungus Penicillium sp. SCSIO 05705 collected nearby the Great Wall station (Chinese Antarctic station) afforded three new indolyl diketopiperazine derivatives, penillines A-B (187-188) and isopenilline A (189) (Figure 31). In the general bioactivity profiling programs including antiviral, cytotoxic, antibacterial and antituberculosis evaluation, all compounds were found inactive [65].     Penicillium granulatum MCCC 3A00475 obtained from the Prydz Bay of Antarctica yielded an unusual spirocyclic diterpene named spirograterpene A (209) (Figure 36). Antiallergic effect was tested in immunoglobulin E-mediated rat mast RBL-2H3 cells and compound 209 was just little weaker active than loratadine at 20 µg/mL [71].

Thermophilic Fungi
Five new polyketides (210-214) ( Figure 37) were produced by Myceliophthora thermophila obtained from the soil of fumaroles in Taiwan. Compounds 210-212 showed cytotoxic activity against A549, Hep3B, MCF-7 and HepG2 cell lines with IC 50 values ranging from 0.25 to 1.30 µg/mL [72]. The EtOAc extract of the mass mycelium and PDA media of Malbranchea sulfurea which was obtained from the soil of fumaroles in Sihchong River Hot Spring Zone, displayed strong cytotoxicity against several cancer cell lines. Further bioassay-guided fractionation and chromatographic separation of the extract led to the isolation of six photosensitive polyketides named malbranpyrroles A-F (215-220) ( Figure 38). Cytotoxic activities against PANC-1, HepG2 and MCF-7 cancer cell lines were tested and IC 50 values for compounds 217-220 ranged from 3 to 11 µM. Flow cytometric measurement for cell cycle analysis showed that when treated by the malbranpyrroles the percentage of MCF-7 and HepG2 cells in G0/G1 phase was slightly increased, and the results suggested that these cytotoxic compounds could arrest the two cancer cell lines at G0 phase via inhibiting some cellular signaling pathways. According to the structure-bioactivity relations, the chlorine atom might be the pharmacophore for cytotoxicity [73].    Clavatustides A-B (233-234) ( Figure 40) containing an unusual anthranilic acid dimer and a D-phenyllactic acid residues were produced by Aspergillus clavatus C2WU isolated from the crab Xenograpsus testudinatus, which lived at extreme, toxic habitat around the sulphur-rich hydrothermal vents in Taiwan Kueishantao. The two novel cyclodepsipeptides significantly suppressed the proliferation of HepG2 cells in a dose-dependent manner, and cell cycle analysis suggested that 233 and 234 could induce G1 arrest and inhibit G1/S phase transition [77].   A hydrothermal vent fungus Penicillium sp. Y-50-10 collected from the sulfur rich sediment (Kueishantao, Taiwan) yielded methyl isoverrucosidinol (244) (Figure 42). This new verrucosidin derivative displayed weak antibiotic activity against Bacillus subtilis with an MIC value of 32 µg/mL [79]. The soil-derived thermophilic fungal strain Aspergillus terreus TM8 collected from a hot desert place (~50 • C) in South Egypt produced a new highly oxygenated tetracyclic meroterpenoid, terretonin M (245) (Figure 43). The crude extract of the mass mycelium and solid rice meida could slightly inhibit the growth of Proteus sp., Candida albicans, and Streptococcus pyogenes, while authors failed to isolate the active ingredient [80].

Halophilic Fungi
Diverse novel compounds have been described from the halotolerant fungal strain Aspergillus variecolor B-17, which was isolated from the sediments collected in Jilantai salt field, Alashan, Inner Mongolia, China.   Three new cerebrosides, alternarosides A-C (265-267) and one new diketopiperazine alkaloid, alternarosin A (268) ( Figure 46) were produced by the halotolerant fungus Alternaria raphani THW-18, which was obtained from a sediment sample in the Hongdao sea salt field, China. Antimicrobial activities against Escherichia coli, Bacillus subtilis, and Candida albicans were evaluated and MIC values for four compounds ranged from 70 to 400 µM. Neither cytotoxicity (P388, HL-60, A549, and BEL-7402 cell lines) nor DPPH radical-scavenging activity was detected [85].    The xerophilic fungus Aspergillus restrictus A-17 obtained from house dust yielded two new dioxopiperazine derivatives, arestrictins A-B (286-287) ( Figure 49). The biological activity of them was not tested [90].
As demonstrated by this review, fungi from extreme environments are a rich source for novel natural products, even though the research on them is not as up-to-date as the research on fungi in other mesophilic environments due to the difficulties in both sample collection and cultivation. However, with the fast development of modern instruments and techniques in the post-genomic era, some groups have obtained many new compounds from one strain by changing its cultivation conditions or creating a mutant, which significantly contributes to make full use of these precious biological resources.

Conflicts of Interest:
The authors declare that they have no conflict of interests.