Asymmetric Synthesis of Pochonin E and F, Revision of Their Proposed Structure, and Their Conversion to Potent Hsp90 Inhibitors
Publication information:
Karthikeyan G, Zambaldo C, Barluenga S, Zoete V, Karplus M, Winssinger N. Asymmetric Synthesis of Pochonin E and F, Revision of Their Proposed Structure, and Their Conversion to Potent Hsp90 Inhibitors. Chemistry - A European Journal. 2012;18(29):8978–8986.
Abstract
A concise and modular synthesis of pochonin E and F, and their epimers at C-6 established the correct stereochem. of these two natural products to be (6R). 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. Mol. dynamics simulations, docking studies, and Hsp90 affinity measurements were performed to evaluate the impact of these modifications.