Alpha-substituted 1-aryl-3-dimethylaminopropanone hydrochlorides: potent cytotoxins towards human WiDr colon cancer cells.
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.
Pati
Hari Narayan
HN
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada.
Das
Umashankar
U
Ramirez-Erosa
Irving Javier
IJ
Dunlop
Donna Mae
DM
Hickie
Robert Allan
RA
Dimmock
Jonathan Richard
JR
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*
D000970:Antineoplastic Agents; D011422:Propionates