A Systematic SAR Study of C10 Modified Paclitaxel Analogues Using a Combinatorial Approach

Authors: Liu Y.; Ali S.M.; Boge T.C.; Georg G.I.; Victory S.; Zygmunt J.; Marquez R.T.; Himes R.H.

Source: Combinatorial Chemistry & High Throughput Screening, Volume 5, Number 1, February 2002 , pp. 39-48(8)

Publisher: Bentham Science Publishers

Abstract:

A library with 63 paclitaxel analogues modified at the C10 position of paclitaxel has been prepared using parallel solution phase synthesis. Most of the C10 analogues were slightly less active than paclitaxel in the tubulin assembly assay and had reduced potency in the B16 melanoma and MCF-7 cell line cytotoxicity assays. These modifications at C10, however, did not lead to the total loss of activity, indicating that the C10 moiety of paclitaxel may not be directly involved in the drug-microtubule interactions, but could influence its binding affinity to P-glycoprotein. Approximately 50 percentof the analogues demonstrated better activity against the drug resistant cell line MCF7-ADR. However, the increase in activity was 10-fold at most. This result demonstrates that the cytotoxicity against this drug resistant cancer cell line is sensitive to structural changes at the C10 position of paclitaxel. It was also found that the presence of a nitrogen atom in the C10 substituent might play a role in the interaction of analogues with microtubules.

Keywords: Paclitaxel Analogues; taxus brevifolia; alzheimer disease; combinatorial chemistry; taxanes; tubulin assembly assay; cell cytotoxicity assay

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1386207023330615

Publication date: 2002-02-01

• Combinatorial Chemistry & High Throughput Screening publishes full length original research articles and reviews describing various topics in combinatorial chemistry (e.g. small molecules, peptide, nucleic acid or phage display libraries) and/or high throughput screening (e.g. developmental, practical or theoretical). Ancillary subjects of key importance, such as robotics and informatics, will also be covered by the journal. In these respective subject areas, Combinatorial Chemistry & High Throughput Screening is intended to function as the most comprehensive and up-to-date medium available. The journal should be of value to individuals engaged in the process of drug discoveryand development, in the settings of industry, academia or government.

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• By this author: Liu Y. ;  Ali S.M. ;  Boge T.C. ;  Georg G.I. ;  Victory S. ;  Zygmunt J. ;  Marquez R.T. ;  Himes R.H.

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