Syntheses, Biological Activity, and Conformational Analysis of Fluorine-Containing Taxoids

Iwao Ojima*, Scott D. Kuduk, John C. Slater, Rayomand H. Gimi, Chung-Ming Sun, Subrata Chakravarty, Michele Ourevitch, Ahmed Abouabdellah, Danièle Bonnet-Delpon, Jean Pierre Bégué, Jean M. Veith, Paula Pera, Ralph J. Bernacki

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

A series of fluorine-containing analogs of paclitaxel and docetaxel are synthesized by coupling (3R,4S)-1-acyl-β-lactams of high enantiomeric purity with properly protected baccatin III, 10-deacetylbaccatin III, and 14β-hydroxy-10-deacetyl-baccatin III as the key step. 3′-Trifluoromethyl-10-acetyl analog of docetaxel is synthesized through highly efficient kinetic resolution of racemic 1-(t-Boc)-4-CF3-β-lactam in the coupling reaction with 7-TES-baccatin III. The 3′-(4-F-C6H4), 3′'-(4-F-C6H4)-10-Ac, and 3′-CF3-10-Ac analogs of docetaxel exhibit better cytotoxicity than paclitaxel, and the 3′-CF3-10-Ac analog possesses more than one order of magnitude higher potency than paclitaxel and docetaxel against a drug-resistant human breast cancer cell line. This analog can be regarded as an excellent lead for the second generation taxoid anticancer agents. Difluoro-paclitaxel, bearing fluorine labels at the 3′-(4-F-C6H4CONH) and 3′-(4-F-C6H4) moieties, is proved to be very useful for the conformational analysis of paclitaxel in solution using 19F NMR. A combination of 19F and 1H variable temperature NMR measurements of the 19F chemical shifts and JH2′-H3′ values as well as molecular modeling including restrained molecular dynamics has identified three key conformers including the one that has never been predicted by the previous molecular modeling and NMR studies. This conformation might be the molecular structure first recognized by the β-tubulin binding site on microtubules.

Original languageEnglish
Pages (from-to)228-243
Number of pages16
JournalACS Symposium Series
Volume639
DOIs
StatePublished - 13 Aug 1996

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