Clomiphene Analogs with Activity In Vitro and In Vivo against Human Breast Cancer Cells

Abstract

Six hundred triphenylethylenes were assayed for antiproliferative activity against MCF-7, LY2, and MDA-MB-231 breast cancer cells using sulforhodamine B dye to measure proliferation. Here we report on just 63 of the compounds, mostly clomiphene analogs, with substitutions on the α′ or β ring, at the vinyl position or in the side chain, of which 23 were active, as defined by antiproliferation ic 50 values ≤1 μM. Activity profiles showed that 23 and 11 analogs were active toward MCF-7 and LY2, respectively, but none were active against MDA-MB-231. The ic 50 values of tamoxifen were 2.0 μM against MCF-7 and 7.5 μM against LY2 and MDA-MB-231. Estradiol reversed antiproliferative activities of several E isomers but not their Z isomer counterparts. Clomiphene side chain analogs 46 [( E)-1-butanamine, 4-[4-(2-chloro-1,2-diphenylethenyl) phenoxy]- N, N-diethyl-dihydrogen citrate (MDL 103,323)] and 57 [( E)- N-[ p-(2-chloro-1,2-diphenylvinyl) phenyl]- N, N-diethylethylenediamine dihydrogen citrate (MDL 101,986)] were 4- to 5-fold more effective than tamoxifen. Methylene additions up to (CH 2) 12 in the clomiphene side chain showed that analog 46 [(CH 2) 4 side chain] had maximal antiproliferative activity, binding affinity, and inhibition of transcription of an estrogen response element luciferase construct in transfected MCF-7 cells. Intraperitoneal administration of 46 or 57 inhibited progression of MCF-7 breast tumor xenografts in nude mice with ed 50 values of <0.02 mg/mouse/day. Both analogs may hold promise for treating ER positive breast cancer and are of interest for further development.