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Design and synthesis of (+)-discodermolide-paclitaxel hybrids leading to enhanced biological activity.

ABSTRACT: 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.

SUBMITTER: Smith AB

PROVIDER: S-EPMC3174350 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Design and synthesis of (+)-discodermolide-paclitaxel hybrids leading to enhanced biological activity.

Smith Amos B AB Sugasawa Keizo K Atasoylu Onur O Yang Chia-Ping Huang CP Horwitz Susan Band SB

Journal of medicinal chemistry 20110826 18

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 inc ...[more]

PMID: 21870795

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