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Design, Synthesis, and Biological Evaluation of HSP90 Inhibitors Based on Conformational Analysis of Radicicol and Its Analogues

Authors
Moulin, Emilie
Zoete, Vincent
Barluenga, Sofia
Karplus, Martin
Published in Journal of the American Chemical Society. 2005, vol. 127, no. 19, p. 6999-7004
Abstract The molecular chaperone HSP90 is an attractive target for chemotherapy because its activity is required for the functional maturation of a number of oncogenes. Among the know inhibitors, radicicol, a 14-member macrolide, stands out as the most potent. A molecular dynamics/minimization of radicicol showed that there were three low energy conformers of the macrocycle. The lowest of these is the bioactive conformation observed in the cocrystal structure of radicicol with HSP90. Corresponding conformational analyses of several known analogues gave a good correlation between the bioactivity and the energy of the bioactive conformer, relative to other conformers. Based on this observation, a number of proposed analogues were analyzed for their propensity to adopt the bioactive conformation prior to synthesis. This led to the identification of pochonin D, a recently isolated secondary metabolite of Pochonia chlamydosporia, as a potential inhibitor of HSP90. Pochonin D was synthesized using polymer-bound reagents and shown to be nearly as potent an HSP90 inhibitor as radicicol.
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Article (Published version) (375 Kb) - document accessible for UNIGE members only Limited access to UNIGE
Other version: http://pubs.acs.org/doi/abs/10.1021/ja043101w
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MOULIN, Emilie et al. Design, Synthesis, and Biological Evaluation of HSP90 Inhibitors Based on Conformational Analysis of Radicicol and Its Analogues. In: Journal of the American Chemical Society, 2005, vol. 127, n° 19, p. 6999-7004. https://archive-ouverte.unige.ch/unige:24524

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Deposited on : 2012-12-12

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