RATIONALLY DESIGNED ANALOGS OF TAMOXIFEN WITH IMPROVED CALMODULIN ANTAGONISM

Computerized molecular modeling studies on the interactions of the ant iestrogen tamoxifen (1) and its analogues bound to the calcium-binding protein calmodulin have guided the rational design of more potent ant agonists. Compounds with either three or four methylene units in the b asic side chain or slim lipophilic 4-substituents were expected to be more potent. All compounds were tested for antagonism of the calmoduli n-dependent activity of cAMP phosphodiesterase and for binding affinit y to the estrogen receptor from rat uteri. Some compounds were assayed for cytotoxicity against MCF-7 breast tumor cells in vitro. Introduct ion of lipophilic 4-substituents was accomplished by using palladium(0 )-catalyzed coupling reactions with a 4-iodinated precursor. Both the 4-ethynyl (16 and 17) and 4-butyl (18 and 19) compounds were more pote nt calmodulin antagonists than tamoxifen. Extension of the basic amino ethoxy side chain of 4-iodotamoxifen (3) and idoxifene (2) ethoxy]phen yl]-1-(4-iodophenyl)-2-phenyl-1-butene) by one or two methylene units resulted in modest gains in calmodulin antagonism (10-13). All the com pounds assayed retained estrogen receptor binding characteristics. The compound possessing the optimal combination of calmodulin antagonism and estrogen receptor binding was 12 ((E)-1-[4-[3-(N-pyrrolidino)propo xy]phen 1-(4-iodophenyl)-2-phenyl-1-butene) (IC50 = 1.1 mu M, RBA = 23 ). Correlation between calmodulin antagonism and cytotoxicity was demo nstrated for selected compounds.'