Unexpectedly Facile Hydrolysis of the 2-Benzoate Group of Taxol and Syntheses of Analogs with Increased Activities

Chaudhary, Ashok; Gharpure, Milind M.; Rimoldi, John M.; Chordia, Mahendra D.; Kingston, David G. I.; Grover, S. K.; Lin, Chii M.; Hamel, Ernest; Gunatilaka, A. A. Leslie

doi:10.1021/ja00088a063

Cited by 94 publications

(60 citation statements)

References 1 publication

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“…Fourth, extension of the C-4 acetate by longer alkyl chains without loss of activity (43) is explained by the location of the C-4 methyl at the top of a deep hydrophobic cleft. Fifth, meta substitution in the phenyl of the C-2 side-chain enhances activity, whereas para substitution reduces it (44). The hydrophobic subsite housing this phenyl moiety is relatively tight on three sides of the ring but open at one of the meta positions.…”

Section: Methodsmentioning

confidence: 99%

The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

Snyder

Nettles²,

Cornett³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

363

396

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The chemotherapeutic drug Taxol is known to interact within a specific site on ␤-tubulin. Although the general location of the site has been defined by photoaffinity labeling and electron crystallography, the original data were insufficient to make an absolute determination of the bound conformation. We have now correlated the crystallographic density with analysis of Taxol conformations and have found the unique solution to be a T-shaped Taxol structure. This T-shaped or butterfly structure is optimized within the ␤-tubulin site and exhibits functional similarity to a portion of the B9-B10 loop in the ␣-tubulin subunit. The model provides structural rationalization for a sizeable body of Taxol structureactivity relationship data, including binding affinity, photoaffinity labeling, and acquired mutation in human cancer cells.

show abstract

Section: Methodsmentioning

confidence: 99%

The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

Snyder

Nettles²,

Cornett³

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

363

396

View full text Add to dashboard Cite

show abstract

“…Materials-PTX, its C-2 analog 2-debenzoyl-2-meta-azidobenzoylpaclitaxel (19), and epothilone B (EPO B) were obtained from the Drug Synthesis and Chemistry Branch of NCI, National Institutes of Health. Vinblastine was from Sigma, and verapamil was from Knoll pharmaceuticals.…”

Section: Methodsmentioning

confidence: 99%

Paclitaxel-resistant Human Ovarian Cancer Cells Have Mutant β-Tubulins That Exhibit Impaired Paclitaxel-driven Polymerization

Giannakakou¹,

Sackett²,

Kang³

et al. 1997

Journal of Biological Chemistry

643

583

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“…This analog is formed by removing the 2-benzoate group of taxol and subsequently reacylating with certain meta-substituted benzoic acids. 43 …”

Section: Structure Activitymentioning

confidence: 99%

Camptothecin and taxol: Discovery to clinic

1998

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Unexpectedly Facile Hydrolysis of the 2-Benzoate Group of Taxol and Syntheses of Analogs with Increased Activities

Cited by 94 publications

References 1 publication

The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density

Paclitaxel-resistant Human Ovarian Cancer Cells Have Mutant β-Tubulins That Exhibit Impaired Paclitaxel-driven Polymerization

Camptothecin and taxol: Discovery to clinic

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