Precursor-Directed Biosynthesis Mediated Amplification of Minor Aza Phenylpropanoid Piperazines in an Australian Marine Fish-Gut-Derived Fungus, Chrysosporium sp. CMB-F214

• Published in: Marine drugs 2021-08, Vol.19 (9), p.478
• Main Authors: Elbanna, Ahmed H, Agampodi Dewa, Amila, Khalil, Zeinab G, Capon, Robert J
• Format: Article
• Language: English
• Subjects: Agar; Animals; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; Australia; Aza Compounds - chemistry; Aza Compounds - metabolism; Aza Compounds - pharmacology; azachrysosporazines; Bacteria - drug effects; Bacteria - growth & development; Bioreactors; Biosynthesis; Candida albicans - drug effects; Candida albicans - growth & development; Cell culture; Cell Line, Tumor; Cell Survival - drug effects; Cells; Chemical analysis; chrysosporazines; Chrysosporium; Chrysosporium - metabolism; Chrysosporium sp; Colon; Cultivation; Cytotoxicity; Doxorubicin; Doxorubicin - pharmacology; Drug Resistance, Neoplasm - drug effects; Fish; Fungi; Gastrointestinal Tract - microbiology; Glycoproteins; Humans; Marine fish; marine fish-gut-derived fungus; Marine fishes; Metabolites; Natural products; Neoplasms; P-Glycoprotein; phenylpropanoid piperazines; Piperazines - chemistry; Piperazines - metabolism; Piperazines - pharmacology; Precursors; Smegmamorpha - microbiology; Sodium; spirochrysosporazine; Supplements
• ISSN: 1660-3397; 1660-3397
• DOI: 10.3390/md19090478

Chemical analysis of an M1 agar plate cultivation of a marine fish-gut-derived fungus, sp. CMB-F214, revealed the known chrysosporazines A-D ( - ) in addition to a suite of very minor analogues - . A microbioreactor (MATRIX) cultivation profiling analysis failed to deliver cultivation conditions that significantly improved the yields of - ; however, it did reveal that M2 agar cultivation produced the new natural product . A precursor-directed biosynthesis strategy adopting supplementation of a CMB-F214 M1 solid agar culture with sodium nicotinate enhanced production of otherwise inaccessible azachrysposorazines A1 ( ), A2 ( ), B1 ( ), C1 ( ), C2 ( ) and D1 ( ), in addition to four new chrysosporazines; chrysosporazines N-P ( - ) and spirochrysosporazine A ( ). Structures inclusive of absolute configurations were assigned to - based on detailed spectroscopic and chemical analyses, and biosynthetic considerations. Non-cytotoxic to human carcinoma cells, azachrysosporazies - were capable of reversing doxorubicin resistance in P-glycoprotein (P-gp)-overexpressing human colon carcinoma cells (SW620 Ad300), with optimum activity exhibited by the C-2' substituted analogues - .