SYNTHESIS OF ANALOGS OF 2-METHOXYESTRADIOL WITH ENHANCED INHIBITORY EFFECTS ON TUBULIN POLYMERIZATION AND CANCER CELL-GROWTH

A new series of estradiol analogs was synthesized in an attempt to imp rove on the anticancer activity of 2-methoxyestradiol, a naturally occ urring mammalian tubulin polymerization inhibitor. The compounds were evaluated as inhibitors of tubulin polymerization and the binding of [ H-3]colchicine to tubulin, as well as for in vitro cytotoxicity in hum an cancer cell cultures. Overall, the most potent of the new compounds were 2-(2',2',2'-trifluoroethoxy)-6-oximinoestradiol, 2-ethoxy-6-oxim inoestradiol, and 2-ethoxy-6-methoximinoestradiol. These agents lacked significant affinity for the estrogen receptor. The cytotoxicities of the compounds correlated in general with their abilities to inhibit t ubulin polymerization, thus supporting inhibition of tubulin polymeriz ation as the primary mechanism causing inhibition of cell growth.