Biological evaluation and structure-activity relationships of bis-(3-aryl-3-oxo-propyl)-methylamine hydrochlorides and 4-aryl-3-arylcarbonyl-1-methyl-4-piperidinol hydrochlorides as potential cytotoxic agents and their alkylating ability towards cellular glutathione in human leukemic T cells.
Various bis (3-aryl-3-oxo-propyl)methylamine hydrochlorides 1 and their corresponding structural and non-classical isomers 4-aryl-3-arylcarbonyl-1-methyl-4-piperidinols 3 were evaluated against human leukemic T (Jurkat) cells and found to possess significant cytotoxicity. Among the series 1 (bis-Mannich bases) and 3 (corresponding piperidinols), compounds la, 1c and 1e showed cytotoxic potency which was approximately 1.6, 3.7 and 3.4 times that of the reference drug 5-fluorouracil, respectively. Except for compound 1d, conversion of bis-Mannich bases to their corresponding piperidinols 3a, 3b and 3e lowered the potency. Besides chloro derivative 1d, bis-Mannich bases displayed greater cytotoxicity compared with their mono-Mannich bases, series 5. Representative bis-Mannich bases (1a, 1e) and piperidinols (3a, 3e) decreased the glutathione level of Jurkat cells. Molecular modeling was utilized in order to evaluate whether the shape, size, critical volume, solvent accessible area and partition coefficient of the different compounds had contributed to the varying potencies observed. Bis-Mannich bases 1a, 1c and 1e may serve as candidate anticancer agents for future development.
Gul
Mustafa
M
Department of Physiology, Faculty of Medicine, University of Kuopio, Kuopio, Finland.
Gul
Halise Inci
HI
Das
Umashankar
U
Hanninen
Osmo
O
D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000494:pharmacology*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D007928:Lethal Dose 50; D015458:Leukemia, T-Cell / Q000473:pathology*; D008352:Mannich Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008744:Methylamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D018906:Antineoplastic Agents, Alkylating; D008352:Mannich Bases; D008744:Methylamines; D010880:Piperidines; D005978:Glutathione