SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NONAROMATIC TAXOIDS- EFFECTS OF ALKYL AND ALKENYL ESTER GROUPS ON CYTOTOXICITY

Several new nonaromatic taxoids are synthesized by means of the beta-l actam synthon method. These include taxoids modified with 3-methylbut- 2-enoate, 3-methylbutanoate, and cyclohexanecarboxylate groups in plac e of the benzoate at the C-2 position. In addition, taxoids with 2-met hylprop-1-enyl, 2-methylpropyl, (E)-prop-1-enyl, and cyclohexyl groups at the C-3' position are also prepared in combination with the modifi cations at C-2. The alkyl and alkenyl ester groups at C-2 displayed pr onounced effects on the in vitro cytotoxicity. Two of the fully alipha tic taxoids possess similar or stronger activity than paclitaxel and d ocetaxel. It is clear that the 2-benzoate does not play a unique role, and replacement with the appropriate alkyl and alkenyl groups provide s taxoids with equivalent or superior activity.