Chrysosporazines F–M: P‑Glycoprotein Inhibitory Phenylpropanoid Piperazines from an Australian Marine Fish Derived Fungus, Chrysosporium sp. CMB-F294

• Published in: Journal of natural products (Washington, D.C.) Vol. 83; no. 2; pp. 497 - 504
• Main Authors: Mohamed, Osama G, Salim, Angela A, Khalil, Zeinab G, Elbanna, Ahmed H, Bernhardt, Paul V, Capon, Robert J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society and American Society of Pharmacognosy 28.02.2020; Amer Chemical Soc
• Subjects: Alkaloids - chemistry; Alkaloids - isolation & purification; Alkaloids - pharmacology; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1 - chemistry; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Australia; Chemistry, Medicinal; Chrysosporium - chemistry; Chrysosporium - drug effects; Colonic Neoplasms - drug therapy; Doxorubicin - pharmacology; Drug Resistance, Multiple - drug effects; Enzyme Inhibitors - pharmacology; Fungi - chemistry; Fungi - drug effects; Humans; Life Sciences & Biomedicine; Molecular Structure; Pharmacology & Pharmacy; Piperazines - chemistry; Plant Sciences; Science & Technology; Structure-Activity Relationship; Australia
• ISSN: 0163-3864; 1520-6025
• DOI: 10.1021/acs.jnatprod.9b01181

Chemical analysis of the fungus Chrysosporium sp. CMB-F294 isolated from the gastrointestinal tract of a market-purchased specimen of Mugil mullet yielded eight new alkaloids, belonging to a rare class of phenylpropanoid piperazines. Chrysosporazines F–M (1–8) occur as an equilibrium mixture of acetamide rotamers and feature unprecedented carbocyclic and heterocyclic scaffolds. Structures inclusive of absolute configuration were assigned by detailed spectroscopic analysis, supported by biosynthetic considerations. Structure–activity relationship studies determined that selected chrysosporazines were promising noncytotoxic inhibitors of the multidrug resistance efflux pump P-glycoprotein (P-gp), capable of reversing doxorubicin resistance in P-gp-overexpressing human colon carcinoma cells (SW620 Ad300). Chrysosporazine F (1) was particularly noteworthy, with a 2.5 μM cotreatment inducing a doxorubicin gain in sensitivity (GS 14) > 2-fold that of the positive control verapamil (GS 6.1).