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-breast cancer agent in rodents and in cell culture. We recently determined that 1 inhibits tubulin assembly in vitro and causes microtubule loss in breast cancer cells, leading to accumulation in the G2/M portion of the cell cycle. Aryl ring-halogenated, methoxylated and benzyloxylated derivatives of 1, as well as its E-isomer and the dichlorocyclopropyl derivative of diethylstilbestrol (DES), were synthesized and tested for their ability to inhibit, the assembly of tubulin into microtubules. Including 1, 17 cyclopropyl compounds were tested. One (Z-1,1-dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane (12)) was found to be more active than 1. In addition, E-1,1-dichlorocyclopropylDES (17) was more potent than DES. The E-isomer of 1 (16) was inactive. The cytostatic activities of the compounds against MCF-7 and MDA-MB231 human breast cancer cells, and their abilities to perturb microtubules in MCF-7 cells were also evaluated. Z-Dichloro-2-(4-fluorophenyl)-3-phenylcyclopropane (5), Z-1,1-dichloro-2-(4-fluorophenyl)-3-(4-methoxyphenyl)cyclopropane (11), and Z-1,1-dichloro-2-(4-methoxyphenyl)-3-phenylcyclopropane (12) were more potent than 1 against the breast cancer cells.
Jonnalagadda
S S
SS
Department of Environmental and Occupational Health, University of Pittsburgh, PA 15238, USA.
ter Haar
E
E
Hamel
E
E
Lin
C M
CM
Magarian
R A
RA
Day
B W
BW
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D002417:Cattle; D002453:Cell Cycle; D002455:Cell Division / Q000187:drug effects; D002853:Chromatography, Liquid; D003078:Colchicine / Q000378:metabolism; D003521:Cyclopropanes / Q000737:chemistry / Q000378:metabolism; D004054:Diethylstilbestrol / Q000737:chemistry; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D011108:Polymers; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003521:Cyclopropanes; D011108:Polymers; D050257:Tubulin Modulators; D004054:Diethylstilbestrol; C030797:cyclopropane; D003078:Colchicine