title: Alpha-substituted 1-aryl-3-dimethylaminopropanone hydrochlorides: potent cytotoxins towards human WiDr colon cancer cells.
abstract: A series of 1-aryl-2-dimethylaminomethyl-2-propenone hydrochlorides 1 were prepared which possessed IC(50) values of less than 10 microM 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.
authors.affiliation: College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada.
authors.forename: Hari Narayan
authors.initials: HN
authors.lastname: Pati
authors.forename: Umashankar
authors.initials: U
authors.lastname: Das
authors.forename: Irving Javier
authors.initials: IJ
authors.lastname: Ramirez-Erosa
authors.forename: Donna Mae
authors.initials: DM
authors.lastname: Dunlop
authors.forename: Robert Allan
authors.initials: RA
authors.lastname: Hickie
authors.forename: Jonathan Richard
authors.initials: JR
authors.lastname: Dimmock
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011422:Propionates / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011422:Propionates