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

Amos B. Smith; Keizo Sugasawa; Onur Atasoylu; Chia Ping Huang Yang; Susan Band Horwitz

doi:10.1021/jm200692n

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

Amos B. Smith, Keizo Sugasawa, Onur Atasoylu, Chia Ping Huang Yang, Susan Band Horwitz

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

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.

Original language	English (US)
Pages (from-to)	6319-6327
Number of pages	9
Journal	Journal of Medicinal Chemistry
Volume	54
Issue number	18
DOIs	https://doi.org/10.1021/jm200692n
State	Published - Sep 22 2011

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/jm200692n

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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.",

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AU - Yang, Chia Ping Huang

AU - Horwitz, Susan Band

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AB - 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.

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

Abstract

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