A common pharmacophore for taxol and the epothilones based on the biological activity of a taxane molecule lacking a C-13 side chain

Lifeng He, Prakash G. Jagtap, David G I Kingston, Heng Jia Shen, George A. Orr, Susan Band Horwitz

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Abstract

Extensive structure-activity studies done with Taxol have identified the side chain at C-13 as one of the requirements for biological activity. Baccatin III, an analogue of Taxol lacking the C-13 side chain, has none of the biological characteristics of Taxol. Since 2-m-azido Taxol, a Taxol derivative with a m-azido substituent in the C-2 benzoyl ring, has greater activity than Taxol, we questioned whether 2-m-azido baccatin III might be active. 2-m-Azido baccatin III inhibited the proliferation of human cancer cells at nanomolar concentrations, blocked cells at mitosis, and reorganized the interphase microtubules into distinct bundles, a typical morphological change induced by Taxol. In contrast to 2-m-azido baccatin III, 2-p-azido baccatin III was similar to baccatin III, having no Taxol-like activity, further indicating the specificity and significance of the 2-meta position substituent. Molecular modeling studies done with the C-2 benzoyl ring of Taxol indicated that it fits into a pocket formed by His227 and Asp224 on β- tubulin and that the 2-m-azido, in contrast to the 2-p-azido substituent, is capable of enhancing the interaction between the benzoyl group and the side chain of Asp224. The observation that the C-13 side chain is not an absolute requirement for biological activity in a taxane molecule has enabled the development of a new common pharmacophore model between Taxol and the epothilones.

Original languageEnglish (US)
Pages (from-to)3972-3978
Number of pages7
JournalBiochemistry
Volume39
Issue number14
DOIs
StatePublished - Apr 11 2000

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Epothilones
Paclitaxel
Bioactivity
Molecules
taxane
Interphase
Molecular modeling
Tubulin
Mitosis
Microtubules
baccatin III

ASJC Scopus subject areas

  • Biochemistry

Cite this

A common pharmacophore for taxol and the epothilones based on the biological activity of a taxane molecule lacking a C-13 side chain. / He, Lifeng; Jagtap, Prakash G.; Kingston, David G I; Shen, Heng Jia; Orr, George A.; Band Horwitz, Susan.

In: Biochemistry, Vol. 39, No. 14, 11.04.2000, p. 3972-3978.

Research output: Contribution to journalArticle

He, Lifeng ; Jagtap, Prakash G. ; Kingston, David G I ; Shen, Heng Jia ; Orr, George A. ; Band Horwitz, Susan. / A common pharmacophore for taxol and the epothilones based on the biological activity of a taxane molecule lacking a C-13 side chain. In: Biochemistry. 2000 ; Vol. 39, No. 14. pp. 3972-3978.
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