Design and Synthesis of (+)-Discodermolide-Paclitaxel Hybrids Leading to Enhanced Biological Activity1

Potential binding modes of (+)-discodermolide at the paclitaxel binding site of tubulin have been identified by computational studies based on earlier structural and SAR data. Examination of the prospective binding modes reveal that the aromatic pocket occupied by the paclitaxel side-chain is unoccu...

Full description

Saved in:
Bibliographic Details
Published inJournal of medicinal chemistry Vol. 54; no. 18; pp. 6319 - 6327
Main Authors Smith, Amos B., Sugasawa, Keizo, Atasoylu, Onur, Yang, Chia-Ping Huang, Horwitz, Susan Band
Format Journal Article
LanguageEnglish
Published 26.08.2011
Online AccessGet full text

Cover

More Information
Summary:Potential binding modes of (+)-discodermolide at the paclitaxel binding site of tubulin have been identified by computational studies based on earlier structural and SAR data. Examination of the prospective binding modes reveal that the aromatic pocket occupied by the paclitaxel side-chain is unoccupied by (+)-discodermolide. Based on these findings, a small library of (+)-discodermolide-paclitaxel hybrids have been designed and synthesized. Biological evaluation reveals a two- to eight- fold increase in antiproliferative activity compared to the parent molecule using the A549 and MCF-7 cancer cell lines.
Bibliography:Current affiliation: Astellas Pharma Inc., Tsukuba-shi, Ibaraki 305-8585, Japan
ISSN:0022-2623
1520-4804
DOI:10.1021/jm200692n