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Mccrearamycins A–D, Geldanamycin‐Derived Cyclopentenone Macrolactams from an Eastern Kentucky Abandoned Coal Mine Microbe
Author(s) -
Wang Xiachang,
Zhang Yinan,
Ponomareva Larissa V.,
Qiu Qingchao,
Woodcock Ryan,
Elshahawi Sherif I.,
Chen Xiabin,
Zhou Ziyuan,
Hatcher Bruce E.,
Hower James C.,
Zhan ChangGuo,
Parkin Sean,
Kharel Madan K.,
Voss S. Randal,
Shaaban Khaled A.,
Thorson Jon S.
Publication year - 2017
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201612447
Subject(s) - cyclopentenone , geldanamycin , derivatization , chemistry , biocatalysis , cytotoxicity , biochemistry , streptomyces , stereochemistry , hsp90 , biology , in vitro , organic chemistry , gene , bacteria , ionic liquid , heat shock protein , high performance liquid chromatography , genetics , catalysis
Abstract Four cyclopentenone‐containing ansamycin polyketides (mccrearamycins A–D), and six new geldanamycins (Gdms B–G, including new linear and mycothiol conjugates), were characterized as metabolites of Streptomyces sp. AD‐23‐14 isolated from the Rock Creek underground coal mine acid drainage site. Biomimetic chemical conversion studies using both simple synthetic models and Gdm D confirmed that the mccrearamycin cyclopentenone derives from benzilic acid rearrangement of 19‐hydroxy Gdm, and thereby provides a new synthetic derivatization strategy and implicates a potential unique biocatalyst in mccrearamycin cyclopentenone formation. In addition to standard Hsp90α binding and cell line cytotoxicity assays, this study also highlights the first assessment of Hsp90α modulators in a new axolotl embryo tail regeneration (ETR) assay as a potential new whole animal assay for Hsp90 modulator discovery.