Syntheses and stability studies of some Mannich bases of acetophenones and evaluation of their cytotoxicity against Jurkat cells.
Mannich bases, namely 1-aryl-3-dimethylamino-1-propanone hydrochlorides (Ia-f) as mono-Mannich bases (series I), bis(beta-aroylethyl)ethylamine hydrochlorides (IIa, IIb, IId, IIe) as bis-Mannich bases (series II), 3-aroyl-4-aryl-1-ethyl-4-piperidinol hydrochlorides (series III), which are structural isomers of bis derivatives and some representative quaternary salts (Ig, IIIf, IIIg), were synthesized to investigate the effect of chemical structure and ring substituents on cytotoxic activity in Jurkat cells. Stability studies of some representative compounds have also been realised. Compounds IIb, IId, IIe, and IIIe were reported for the first time. Id-g, IIa, IId, IIe, IIIf,g were 1.25-6.55 times more potent than 5-fluorouracil (CAS 51-21-8). However, the cytotoxic activity of the most potent compounds. Ig and IIIf, were one fifth of that of melphalan (CAS 148-82-3). The formation of compound IV during the stability studies of Ig, IIa, and IIIf suggested that they may be thiol alkylators. Bis-Mannich base IIa in nonsubstituted derivatives, piperidinol derivative IIIb in methyl substituted compounds, mono derivative Id in chloro substituted compounds were the most potent compounds when the cytotoxicity of the compound series which have the same substituents in benzene ring are compared. Replacement of the benzene with thiophene improved the cytotoxicity in both series I and II. Quaternization procedure also increased the cytotoxicity in both series I and III. Quaternary derivatives seem to be promising compounds for further studies to develop new anticancer drugs.
Gul
Halise Inci
HI
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University, Izmir, Turkey. incigul@mailcity.com
Gul
Mustafa
M
Erciyas
Ercin
E
D000098:Acetophenones / Q000138:chemical synthesis* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003500:Cyclization; D004355:Drug Stability; D006801:Humans; D007202:Indicators and Reagents; D019169:Jurkat Cells; D008352:Mannich Bases / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000098:Acetophenones; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D008352:Mannich Bases