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Asymmetric Synthesis of Pochonin E and F, Revision of Their Proposed Structure, and Their Conversion to Potent Hsp90 Inhibitors
Author(s) -
Karthikeyan Ganesan,
Zambaldo Claudio,
Barluenga Sofia,
Zoete Vincent,
Karplus Martin,
Winssinger Nicolas
Publication year - 2012
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201200546
Subject(s) - epimer , hsp90 , stereochemistry , heat shock protein , docking (animal) , chemistry , hsp90 inhibitor , combinatorial chemistry , biochemistry , medicine , nursing , gene
A concise and modular synthesis of pochonin E and F, and their epimers at C‐6 established the correct stereochemistry of these two natural products. Several members of the pochonin family have been shown to bind the heat shock protein 90 (Hsp90), which has been the focus of intense drug discovery efforts. Pochonin E and F as well as their epimers were derivatized into the corresponding pochoximes and further modified at the C‐6 position. Molecular dynamics simulations, docking studies, and Hsp90 affinity measurements were performed to evaluate the impact of these modifications.