4-(beta-Arylvinyl)-3-(beta-arylvinylketo)-1-ethyl-4-piperidinols and related compounds: a novel class of cytotoxic and anticancer agents.
The syntheses of a series of 1-aryl-5-diethylamino-1-penten-3-one hydrochlorides 1 and 1-aryl-3-diethylamino-1-propanone hydrochlorides 4 were accomplished. Attempts to prepare the corresponding bis(5-aryl-3-oxo-4-pentenyl)ethylamine hydrochlorides 2 and bis(3-aryl-3-oxopropyl)ethylamine hydrochlorides 5 led to the formation of a series of 4-(beta-arylvinyl)-3-(beta-arylvinylketo)-1-ethyl-4-piperidi nol hydrochlorides 9 and 4-aryl-3-arylketo-1-ethyl-4-piperidinol hydrochlorides 11, most of which were converted subsequently into the corresponding quaternary ammonium salts 10 and 12, respectively. The structures of these compounds were determined by 1H NMR spectroscopy and confirmed by X-ray crystallography of representative molecules. Most compounds displayed significant cytotoxicity toward murine P388 and L1210 cells as well as human tumors. In general, Mannich bases containing olefinic bonds were more cytotoxic than the analogues without this functional group, while the piperidines 9 and 11 were more potent than the acyclic analogues 1 and 4, respectively. Correlations were noted between various physicochemical constants in the aryl rings and cytotoxicity. Compound 9d displayed promising in vivo activity against colon cancers. This study has revealed that the piperidines 9 and 11 constitute new classses of cytotoxic agents.
Dimmock
J R
JR
College of Pharmacy and Nutrition, Department of Chemistry, and Department of Biochemistry, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada.
Vashishtha
S C
SC
Quail
J W
JW
Pugazhenthi
U
U
Zimpel
Z
Z
Sudom
A M
AM
Allen
T M
TM
Kao
G Y
GY
Balzarini
J
J
De Clercq
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D007939:Leukemia L1210 / Q000473:pathology; D007941:Leukemia P388 / Q000473:pathology; D008352:Mannich Bases / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C115066:1-ethyl-3-((4-methylphenyl)-1-oxo-2-propenyl)-4-((4-methylphenyl)ethenyl)piperidine; D000970:Antineoplastic Agents; D008352:Mannich Bases; D010880:Piperidines