α-Substituted 1-Aryl-3-dimethylaminopropanone Hydrochlorides : Potent Cytotoxins towards Human WiDr Colon Cancer Cells

概要

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A series of 1-aryl-2-dimethylaminomethyl-2-propenone hydrochlorides 1 were prepared which possessed IC_<50> values of less than 10μм when examined towards human WiDr colon cancer cells. The related 1-aryl-2-dimethylaminomethyl-3-hydroxypropanone hydrochlorides 2, formed by hydration of the analogs in series 1, also had IC_<50> values in the low micromolar range. On the other hand, conversion of 2-dimethylaminomethyl-1-(4-nitrophenyl)-2-propenone hydrochloride 1c into the corresponding 2-mercaptoethanol of adduct 3c led to a 37-fold reduction in potency. Two thirds of the compounds prepared in this study were more potent than a reference drug cisplatin while one third of these molecules displayed greater cytotoxicity to the WiDr cells than human CRL-2522 fibroblasts. A stability study of the 4-nitrophenyl analog in each of the series 1-3 in deuterium oxide was undertaken. In the case of 1c, replacement of the dimethylamino hydrochloride group by a hydroxy function was noted while in series 2, the loss of both water and dimethylamine hydrochloride gave rise to a mixture of two enones. The mercaptoethanol adduct 3c underwent deamination. The data obtained provide guidelines for amplifying the project in the future.
公益社団法人日本薬学会の論文
2007-04-01