About this item:

449 Views | 0 Downloads

Author Notes:

Correspondence: Weiqiang Zhan, weiqiang.zhan@emory.edu; or James P. Snyder, jsnyder@emory.edu

Acknowledgments: We thank Kenneth Hardcastle (Emory University) for determination of the X-ray crystal structure of compound 19.

Subject:

Research Funding:

The work was supported in part by the NIH Grant No. CA-69571.

Keywords:

  • Epothilone
  • total synthesis
  • modeling
  • natural products
  • antitumor agents

C6 –C8 Bridged Epothilones: Consequences of Installing a Conformational Lock at the Edge of the Macrocycle

Tools:

Journal Title:

Chemistry - A European Journal

Volume:

Volume 17, Number 52

Publisher:

, Pages 14792-14804

Type of Work:

Article | Post-print: After Peer Review

Abstract:

A series of conformationally restrained epothilone analogs with a short bridge between the methyl groups at C6 and C8 was designed to mimic the binding pose assigned to our recently reported EpoA-microtubule binding model. A versatile synthetic route to these bridged epothilone analogs has been successfully devised and implemented. Biological evaluation of the compounds against A2780 human ovarian cancer and PC3 prostate cancer cell lines suggested that the introduction of a bridge between C6-C8 reduced potency by 25–1000 fold in comparison with natural epothilone D. Tubulin assembly measurements indicate these bridged epothilone analogs to be mildly active, but without significant microtubule stabilization capacity. Molecular mechanics and DFT energy evaluations suggest the mild activity of the bridged epo-analogs may be due to internal conformational strain.

Copyright information:

© 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Export to EndNote