C-3′-Cyclopropanated Taxol Analogs: Synthesis, Bioassay and Biostructural Analysis

Ten taxoids with a cyclopropanated side chain were synthesized by coupling a spirocyclopropanated oxazoline-5-carboxylic acid with 7-(triethylsilyl)baccatin III, followed by hydrolytic ring opening and benzoyl migration. The absolute configuration of the 2′-position was determined by NMR analysis of the corresponding Mosher esters. These paclitaxel analogs were active in A2780 mammalian and PC-3 prostate cancer cell lines, and also in a tubulin-assembly assay, but all the analogs were less active than paclitaxel itself. To probe the basis for the uniform potency reduction shown by the cyclopropanated taxoid series, we have examined the conformational properties of compound 3b alone by molecular mechanics and in complex with tubulin by molecular dynamics. In addition, we have performed an NMR/NAMFIS conformer deconvolution analysis for compound 3b. Both modeling and NAMFIS approaches provide a satisfying understanding of the biological behavior of the series of cyclopropanated taxoids and provide further, though indirect, support for the T-form as characteristic of taxoids bound to β-tubulin. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)