Condensation of Macrocyclic Polyketides Produced by Penicillium sp. DRF2 with Mercaptopyruvate Represents a New Fungal Detoxification Pathway

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• 作者：Marcos V. de Castro ; Laura P. Ióca ; David E. Williams ; Bruna Z. Costa ; Carolina M. Mizuno ; Mario F. C. Santos ; Karen de Jesus ; Éverton L. F. Ferreira ; Mirna H. R. Seleghim ; Lara D. Sette ; Edenir R. Pereira Filho ; Antonio G. Ferreira ; Natália S. Gonçalves ; Raquel A. Santos ; Brian O. Patrick ; Raymond J. Andersen ; Roberto G. S. Berlinck
• 刊名：Journal of Natural Products
• 出版年：2016
• 出版时间：June 24, 2016
• 年：2016
• 卷：79
• 期：6
• 页码：1668-1678
• 全文大小：449K
• 年卷期：0
• ISSN：1520-6025

文摘

Application of a refined procedure of experimental design and chemometric analysis to improve the production of curvularin-related polyketides by a marine-derived Penicillium sp. DRF2 resulted in the isolation and identification of cyclothiocurvularins 6–8 and cyclosulfoxicurvularins 10 and 11, novel curvularins condensed with a mercaptolactate residue. Two additional new curvularins, 3 and 4, are also reported. The structures of the sulfur-bearing curvularins were unambiguously established by analysis of spectroscopic data and by X-ray diffraction analysis. Analysis of stable isotope feeding experiments with [U–¹³C₃¹⁵N]-l-cysteine confirmed the presence of the 2-hydroxy-3-mercaptopropanoic acid residue in 6–8 and the oxidized sulfoxide in 10 and 11. Cyclothiocurvularins A (6) and B (7) are formed by spontaneous reaction between 10,11-dehydrocurvularin (2) and mercaptopyruvate (12) obtained by transamination of cysteine. High ratios of [U–¹³C₃¹⁵N]-l-cysteine incorporation into cyclothiocurvularin B (7), the isolation of two diastereomers of cyclothiocurvularins, the lack of cytotoxicity of cyclothiocurvularin B (7) and its methyl ester (8), and the spontaneous formation of cyclothiocurvularins from 10,11-dehydrocurvularin and mercaptopyruvate provide evidence that the formation of cyclothiocurvularins may well correspond to a 10,11-dehydrocurvularin detoxification process by Penicillium sp. DRF2.