SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS OF NOVEL 14β-SIDE CHAIN TAXOL DERIVATIVES

In order to develop new generation of taxollike anticancer agents with fewer side effects, improved activity, superior pharmacological properties and broad antitumor spectrum, along with structureactivity relationship study, a series of new taxol derivatives are to be synthesized starting from sinenxan A - a biosynthetic taxane. Eight new 14β-side chain taxol derivatives with 4-OH and 4-Ac were synthesized in 5 and 6 steps from semisynthetic taxoid intermediate 7, respectively. These included taxol derivatives modified at C-2 position with benzoate, m-Cl benzoate, valerate and phenylacetate. All target compounds together with two other 14β-side chain taxol derivatives were tested in a microtubule assembly assay, and in an in vitro cytotoxicity assay (KB, A2780, HCT-8 cell line). All compounds had no effect in the microtubule assembly assay at 10 μmol·L^-1. Most of them showed marginal activity in the in vitro cytotoxicity. The structureactivity relationship was different from taxol derivatives. 2-Aliphatic ester displayed similar activity to 2-aromatic ester, which indicated that the aromatic group at C-2 position was not important for cytotoxicity. Comparing among themselves, 4-OH deravitives possessed stronger activity than 4-Ac.