SYNTHESIS AND BIOLOGICAL EVALUATION OF 1,1-DICHLORO-2,3-DIARYLCYCLOPROPANES AS ANTITUBULIN AND ANTI-BREAST CANCER AGENTS

Z-1,1-Dichloro-2,3-diphenylcyclopropane (1) is an effective 'anti-brea st cancer agent in rodents and in cell culture. We recently determined that 1 inhibits tubulin assembly in vitro. and causes microtubule los s in breast cancer cells, leading to accumulation in the G2/M portion of the cell cycle. Aryl ring-halogenated, methoxylated and benzyloxyla ted derivatives of 1, as well as its E-isomer and the dichlorocyclopro pyl derivative of diethylstilbestrol (DES), were synthesized and teste d for their ability to inhibit the assembly of tubulin into micro tubu les. Including 1, 17 cyclopropyl compounds were tested. One -dichloro- 2-(4-methoxyphenyl)-3-phenylcyclopropane (12)) was found to be more ac tive than 1. In addition, E-1,1-dichlorocyclopropylDES (17) was more p otent than DES. The E-isomer of 1 (16) was inactive. The cytostatic ac tivities of the compounds against MCF-7 and MDA-MB231 human breast can cer cells, and their abilities to perturb microtubules in MCF-7 cells were also evaluated. Z-Dichloro-2-(4-fluorophenyl)-3-phenylcyclo (5), 2-(4-fluorophenyl)-3-(4-methoxyphenyl)cyclopropane (11), and Z-1,1-dic hloro-2-(4-methoxyphenyl) -3-phenylcyclopropane (12) were more potent than 1 against the breast cancer cells. (C) 1997 Elsevier Science Ltd.