Abstract
Chemical analysis of an M1 agar plate cultivation of a marine fish-gut-derived fungus, Chrysosporium sp. CMB-F214, revealed the known chrysosporazines A–D (11–14) in addition to a suite of very minor aza analogues 1–6. A microbioreactor (MATRIX) cultivation profiling analysis failed to deliver cultivation conditions that significantly improved the yields of 1–6; however, it did reveal that M2 agar cultivation produced the new natural product 15. 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 (1), A2 (2), B1 (3), C1 (4), C2 (5) and D1 (6), in addition to four new chrysosporazines; chrysosporazines N–P (7–9) and spirochrysosporazine A (10). Structures inclusive of absolute configurations were assigned to 1–15 based on detailed spectroscopic and chemical analyses, and biosynthetic considerations. Non-cytotoxic to human carcinoma cells, azachrysosporazies 1–5 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 3–5.
Highlights
During prior investigations into Australian marine-derived fungi, we reported on the gastrointestinal tract (GIT) of fresh market-purchased fish (Mugil mullet) as a rich source of taxonomically and chemically diverse fungi
P-gp-overexpressing human colon carcinoma (SW620 Ad300) cells pre-treated with chrysosporazine F (2.5 μM) acquired a gain in sensitivity (GS 14) against the anticancer agent doxorubicin, >2-fold that of the positive control verapamil (GS 6.1), making chrysosporazine F one of the more potent P-gp inhibitors reported to date [5]
We report a precursor-directed biosynthesis strategy where supplementation of a
Summary
During prior investigations into Australian marine-derived fungi, we reported on the gastrointestinal tract (GIT) of fresh market-purchased fish (Mugil mullet) as a rich source of taxonomically and chemically diverse fungi. We report a precursor-directed biosynthesis strategy where supplementation of a. We report a precursor-directed biosynthesis strategy where suppleme tation of a CMB-F214 M1 solid agar culture with sodium nicotinate enhanced producti of otherwise inaccessible new natural products—namely azachrysposorazines A1 (1), CMB-F214 M1 solid agar culture with sodium nicotinate enhanced production of oth(2), B1erwise (3), C1. Structures were assigned to 1–15 (Figure 1) on the basis chrysosporazine Q (15). Structures were assigned to 1–15 (Figure 1) on the basis of detailed detailed spectroscopic and chemical analyses, and biosynthetic considerations. Access spectroscopic and chemical analyses, and biosynthetic considerations. 1–15 facilitated structure–activity relationship on inhibitory the P-gp properties inhibitoryofpropert facilitated a a structure–activity relationship analysisanalysis on the P-gp of this novel class of phenylpropanoid piperazines.
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