Unveiling the Mechanisms of Apoptosis Induction by Deep-Sea-Derived Polyketide-Terpenoid Hybrids from Penicillium allii-sativi:A Focus on Mitochondrial and mTOR Pathways

Comprehensive Summary A chemical investigation of the deep-sea-derived fungus Penicillium allii-sativi MCCC 3A00580 resulted in the discovery of four new meroterpenoids(1—4)and one related known co-metabolite(5).These meroterpenoids showcase unique carbon skeletons featuring a common drimane sesquiterpene part with highly diverse polyketide units.Particularly,compound 1 incorporates a salicylic acid moiety while 2 possesses a rare peroxide bridge in the polyketide part.The structures of new compounds were assigned by extensive spectroscopic analysis,quantum calculations,and biogenetic considerations.Notably,3 significantly blocked the mTOR signaling pathway,resulting in the arrest of cell cycle at G0-G1 phase and triggering mitochondrial apoptosis in Hela cells.While the previously reported co-metabolite macrophorin A(MPA)effectively triggered cell death in MDA-MB-231 cancer cells by activating apoptosis pathways involving death receptors,mitochondria,mTOR,and TNF.

Two glucosylated angucyclines from deep-sea-derived Streptomyces sp.PKU-MA01297

Angucyclines are aromatic polyketides produced by typeⅡpolyketide synthase(PKS)exclusively from actinomycetes.These natural products contain hydrolyzable sugar moieties that attach to various positions of the polyketide skeleton and expand the structural diversity.We here report the isolation of two new angucyclines(1 and 2)from the deep-sea-derived Streptomyces sp.PKU-MA01297,which was isolated from a sediment sample collected at a depth of 3202 meters from the Indian Ocean.The structures of the two new compounds were elucidated based on comprehensive methods,including NMR,MS and CD analysis.Compounds 1 and 2 featured a 1-O-β-D-glucopyranosyl moiety that has not been reported for angucyclines.Several biological activity assays,including antibacterial,cytotoxicity and anti-inflammatory assays,were carried out,and compounds 1 and 2 showed no activities.These results set the stage for biosynthetic research and more biological activity assays in the future.

A new iron(Ⅲ) chelator of coprogen-type siderophore from the deep-sea-derived fungus Mycosphaerella sp. SCSIO z059

Mycosphazine A(1), a new iron(Ⅲ) chelator of coprogen-type siderophore, and mycosphamide A(2), a new cyclic amide benzoate, together with six known aryl amides(3-8), were isolated from the fermentation broth of the deep-sea-derived fungus Mycosphaerella sp. SCSIO z059. Alkaline hydrolysis of 1 afforded a new epimer of dimerum acid, mycosphazine B(1 a), and a new bi-fusarinine-type siderophore, mycosphazine C(1 b). The planar structures of the new compounds were elucidated by extensive spectroscopic data analysis. The absolute configurations of amino acid residues in 1 a and 1 b were determined by acid hydrolysis. And the absolute configuration of 2 was established by quantum chemical calculations of the electronic circular dichroism(ECD) spectra. Compound 1 is the first siderophore-Fe(Ⅲ) chelator incorporating both L-ornithine and D-ornithine unites. Compounds 3-8 were reported as natural products for the first time, and the 1 H and 13 C NMR data of 6 and 8 were assigned for the first time. Compounds 1 and 1 a could greatly promote the biofilm formation of bacterium Bacillus amyloliquefaciens with the rate of about 249% and 524% at concentration of 100 μg·mL-1, respectively.

Hawanoids A–E, unprecedented diterpenoids with PAF-induced platelet aggregation inhibitory activities from the deep-sea-derived fungus Paraconiothyrium hawaiiense

Hawanoids A–E(1–5), five highly cyclized diterpenoids were isolated from the deep-sea-derived fungus Paraconiothyrium hawaiiense FS482. Compounds 1 and 2 possessed an unprecedented tetracyclo[6.6.2.0^(2,7).0^(11,15)]cetane carbon skeleton while 3 and 4 possessed an unusual 11,14-macrocyclic ether moiety in phomactin family. Their structures including the stereo-chemistry were determined through spectroscopic analysis, X-ray diffractions and computational calculations. The plausible biosynthetic pathway was proposed based on the predicted biosynthetic gene cluster. All of the isolated compounds exhibited inhibitory activities against PAF-induced platelet aggregation. The molecular docking study was carried out understand the interaction between the PAF receptor and hawanoids with different skeletons.

Secondary metabolites from a deep-sea-derived Aspergillus versicolor F77

Chemical examination of fermentation products of a deep-sea-derived fungus Aspergillus versicolor F77 led to the isolation of two new compounds acetyl-sydonol(1)and 2-hydroxydiorcinol D(2),a new natural product 1-(2,4-dimethoxyphenyl)-1,2-dihydro-3 H-pyrazol-3-one(3),together with four known compounds sydonol(4),(S)-sydonic acid(5),aspergillusene A(6)and diorcinol D(7).Their structures were determined through the extensive spectroscopic analysis and comparison with the reported data in literature.Compound 6 showed moderate NF-κB inhibitory activity.

Phylogenetic diversity and bioactivity of culturable deepsea-derived fungi from Okinawa Trough

Deep-sea sediments are now recognized as a home for rich and largely microbial community.Recently,it has been believed in an increasing number of studies that bacteria could be abundant in deepsea sediments of many types;however,fungi in deep-sea sediments remain relatively unknown.The phylogenetic diversity and bioactivity of culturable deep-sea-derived fungi from Okinawa Trough sediments were investigated in traditional method combined with fungal identification of molecular biology in this study.A total of 76 isolates belonged to 15 fungal taxa were recovered in a harsh condition of low nutrient and low temperature,indicating that the fungal communities in deep-sea sediments from Okinawa Trough were relatively abundant and diversified.Aspergillus,Cladosporium,and Penicillium were the dominant fungal genera,while Mycosphaerella,Purpureocillium,and Schizophyllum were relatively rare in the deep-sea sediments from Okinawa Trough.Among the six genera recovered,Mycosphaerella was firstly recovered from deep-sea sediments in this study.Moreover,about 75%of the extracts from the 15 fungal representative isolates displayed distinct bioactivity against at least one indicator bacterium or marine macrofouler,emphasizing the potentials of these deep-sea-derived fungi from Okinawa Trough as producers of bioactive metabolites.Notably,isolates Cladosporium oxysporum SCSIO z001 and Penicillium citrinum SCSIO z049 displayed a wide spectrum of bioactivities,isolates Cladosporium cladosporioides SCSIO z015,Cladosporium sphaerospermum SCSIO z030,and Penicillium verruculosum SCSIO z007 exhibited a strong anti-bacterial-growth activity,and isolate Penicillium chrysogenum SCSIO z062 displayed a strong anti-larval-settlement activity.These results suggest that these isolates deserved further study as potential sources of novel bioactive metabolites.