[Synthesis and structure-activity relationships of novel 14 beta-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 14 beta-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 14 beta-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 mumol.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 derivatives possessed stronger activity than 4-Ac.