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.
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This work was supported by National Institutes of Health grants R24 OD21479 (SRV, JST), T32 DA016176 (YZ), the University of Kentucky College of Pharmacy, the University of Kentucky Markey Cancer Center, and the National Center for Advancing Translational Sciences (UL1TR001998).
Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201612447.
Wang, Xiachang; Zhang, Yinan; Ponomareva, Larissa V.; Qiu, Qingchao; Woodcock, Ryan M.; Elshahawi, Sherif I.; Chen, Xiabin; Zhou, Ziyuan; Hatcher, Bruce E.; Hower, James C.; Zhan, Chang-Guo; Parkin, Sean; Kharel, Madan K.; Voss, S. Randal; Shaaban, Khaled A.; and Thorson, Jon S., "Mccrearamycins A-D, Geldanamycin-Derived Cyclopentenone Macrolactams from an Eastern Kentucky Abandoned Coal Mine Microbe" (2017). Center for Pharmaceutical Research and Innovation Faculty Publications. 6.