title: Mccrearamycins A-D, Geldanamycin-Derived Cyclopentenone Macrolactams from an Eastern Kentucky Abandoned Coal Mine Microbe.
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.
authors.affiliation: Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536, USA.
authors.forename: Xiachang
authors.identifier: 0000-0002-1106-1904
authors.initials: X
authors.lastname: Wang
authors.affiliation: Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536, USA.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536, USA.
authors.forename: Larissa V
authors.initials: LV
authors.lastname: Ponomareva
authors.affiliation: Department of Biology, University of Kentucky, Lexington, KY, 40506, USA.
authors.forename: Qingchao
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Department of Biology, University of Kentucky, Lexington, KY, 40506, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Woodcock
authors.affiliation: Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536, USA.
authors.forename: Sherif I
authors.identifier: 0000-0003-1879-1552
authors.initials: SI
authors.lastname: Elshahawi
authors.affiliation: Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536, USA.
authors.forename: Xiabin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536, USA.
authors.forename: Ziyuan
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Kentucky Division of Abandoned Mine Lands, 300 Sower Blvd, Frankfort, KY, 40601, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Hatcher
authors.affiliation: Center for Applied Energy Research, University of Kentucky, Lexington, KY, 40511, USA.
authors.forename: James C
authors.identifier: 0000-0003-4694-2776
authors.initials: JC
authors.lastname: Hower
authors.affiliation: Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536, USA.
authors.forename: Chang-Guo
authors.initials: CG
authors.lastname: Zhan
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, KY, 40506, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Parkin
authors.affiliation: School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, Maryland, 21853, USA.
authors.forename: Madan K
authors.initials: MK
authors.lastname: Kharel
authors.affiliation: Department of Biology, University of Kentucky, Lexington, KY, 40506, USA.
authors.forename: S Randal
authors.initials: SR
authors.lastname: Voss
authors.affiliation: Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536, USA.
authors.forename: Khaled A
authors.initials: KA
authors.lastname: Shaaban
authors.affiliation: Center for Pharmaceutical Research and Innovation, College of Pharmacy, University of Kentucky, Lexington, Kentucky, 40536, USA.
authors.forename: Jon S
authors.identifier: 0000-0002-7148-0721
authors.initials: JS
authors.lastname: Thorson
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003031:Coal / Q000382:microbiology*; D003517:Cyclopentanes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007629:Kentucky; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008968:Molecular Conformation; D013237:Stereoisomerism; D013302:Streptomyces / Q000737:chemistry* / Q000378:metabolism
chemical_list: D003031:Coal; D003517:Cyclopentanes; D018841:HSP90 Heat-Shock Proteins; C533585:HSP90AA2P protein, human; D047029:Lactams, Macrocyclic; C013905:cyclopentenone
keywords: Hsp90; ansamycin; axolotl; biomimetic synthesis; regeneration