SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF NEW ANTITUMOR TAXOIDS - EFFECTS OF CYCLOHEXYL SUBSTITUTION AT THE C-3' AND OR C-2 OF TAXOTERE (DOCETAXEL)/

Synthesis and cytotoxicity of the new analogs (11-13) of docetaxel pos sessing cyclohexyl groups instead of phenyl groups at the C-3' and/or C-2 benzoate positions are described. The C-2 cyclohexanecarboxylate a nalog of paclitaxel(15) is also synthesized for comparison. The potenc y of these new taxoids were examined for their inhibitory activity for microtubule disassembly and also for their cytotoxicity against murin e P388 leukemia cell line as well. as doxorubicin-resistant P388 leuke mia cell line (P388/Dox). It is found that 3'-dephenyl-3'-cyclohexyldo cetaxel (11) (0.72T) and 2-(hexahydro)docetaxel (12) (0.85T) possess s trong inhibitory activity for microtubule disassembly equivalent to do cetaxel (0.7T), which is more potent than paclitaxel (1.0T). The resul ts clearly indicate that phenyl or an aromatic group at C-3' or C-2 is not a requisite for strong binding to the microtubules. This finding has opened an avenue for development of new nonaromatic analogs of doc etaxel and paclitaxel. 3'-Dephenyl-3'-cyclohexyl-2-(hexahydro)docetaxe l (13) (2T) turns out to be a substantially weaker inhibitor. The cyto toxicities of 11-13 against P388 are, however, in the same range that is 8-12 times weaker than docetaxel and 4-6 times weaker than paclitax el, i.e., 13 shows equivalent cytotoxicity to that of 11 or 12 in spit e of much lower microtubule disassembly inhibitory activity. The cytot oxicities of these new taxoids against the P388/Dox cell line are only 2-2.5 times lower than that of docetaxel. The potency of 2-(hexahydro )paclitaxel (15) for these assays is much lower than the docetaxel cou nterpart 12. The significant loss of activity in vivo against B16 mela noma is observed for 11-13, i.e., 11 is only marginal (T/C = 38% at 20 mg/kg/day), and 12 and 13 are inactive (T/C = 76% and 79%, respective ly). This could be ascribed to faster metabolism, faster excretion or other bioavailability problems.