ABSTRACT
Jurkat cells were exposed to representative acetophenone-derived mono Mannich bases 2 and 3 and also cyclic Mannich base C1 in culture conditions to see the alterations in the most abundant cellular thiol, glutathione and also some of the enzymes in its metabolic pathway. Jurkat cells were exposed to the compounds for 24 h in cell culture medium with fetal bovine serum (1%) at 37 degrees C under a humidified atmosphere of 95% air and 5% CO2. Mannich bases generally increased total glutathione level (123-151% of control). Glutathione S-transferase (GST) activity also increased (150-363% of control), while glutathione disulfide reductase (GRD) activity was not affected. The increase in cellular glutathione level may possibly result from de novo glutathione synthesis. The consumption of the glutathione due to alkylation by Mannich bases might have stimulated the enzymes in the gamma-glutamyl cycle in our experimental design, where the cells had nutrients and time to react with their feedback mechanisms. A remarkable increase in GST activity might be a compensatory up-regulation to detoxify Mannich bases by conjugating them with cellular thiols.
Subject(s)
Glutathione Transferase/metabolism , Glutathione/metabolism , Jurkat Cells/drug effects , Jurkat Cells/enzymology , Mannich Bases/toxicity , NADH, NADPH Oxidoreductases/metabolism , Acetophenones/chemistry , Dose-Response Relationship, Drug , Glutathione Reductase , Humans , Jurkat Cells/cytology , Mannich Bases/chemistry , Thioredoxin-Disulfide ReductaseABSTRACT
The effect of the acetophenone derived mono Mannich bases 1-3 and bis Mannich base 7 (bis derivative of compound 3) on cellular glutathione level was investigated in Jurkat cells. The cells were exposed to the compounds in phosphate buffered saline for 1 h in 37 degrees C with gentle shaking and then glutathione level was measured. Especially, mono Mannich base 3 and its bis derivative 7 decreased total glutathione level in a dose-dependent manner. The results provide further support for the thiol alkylation mechanism explaining the cytotoxic activity of Mannich bases.
Subject(s)
Acetophenones/chemistry , Glutathione/metabolism , Mannich Bases/chemistry , Alkylation , Humans , Jurkat CellsABSTRACT
The development of resistance to current antifungal therapeutics drives search for new effective agents. Some Mannich bases have antifungal activity, but no information is available regarding the antifungal activity of acetophenone derived Mannich bases. Mono Mannich bases of acetophenone 1-3 were synthesized and converted into their corresponding bis derivatives, 5-7. Representative quaternary derivatives 4 and 8 were also synthesized. Antifungal activities of the compounds were evaluated using some yeasts and dermatophytes in vitro. Mono Mannich base 3 and quaternary compounds 4 and 8 were found to be 2-16 times more potent than the reference compound amphotericin B against dermatophytes: Trichophyton rubrum, Trichophyton mentagrophytes, and Microsporum canis. Compounds 4 and 8 were also found to be 2 times more effective compared with amphotericin B against the yeast Saccharomyces cerevisiae. Quaternization procedure improved the biological activity dramatically, whereas conversion of mono Mannich bases to corresponding bis derivatives generally did not affect antifungal activity. Our results suggest that acetophenone derived mono Mannich base 3 and quaternary derivatives 4 and 8 may serve as leading compounds for further studies to develop new antifungal agents with their highly potent antifungal activity.
Subject(s)
Acetophenones/pharmacology , Antifungal Agents/pharmacology , Mannich Bases/pharmacology , Acetophenones/chemical synthesis , Antifungal Agents/chemical synthesis , Arthrodermataceae/drug effects , Mannich Bases/chemical synthesis , Microbial Sensitivity Tests , Structure-Activity Relationship , Yeasts/drug effectsABSTRACT
Mannich bases of acetophenones have been disclosed to have antitumour and cytotoxic activities. 1-Phenyl-3-dimethylaminopropan-1-one hydrochloride, 1, and related piperidino, 2, and morpholino, 3, derivatives, and compound 4, which is a quaternary form of 1, were synthesized as mono Mannich bases derived from acetophenone. They were converted to corresponding bis Mannich bases, 5-8, to see whether it increases the bioactivity. The biological activity of the compounds was examined by cytotoxicity against mouse renal carcinoma (Renca) and transformed human T-lymphocyte (Jurkat) cell lines. Conversion of mono Mannich bases to corresponding bis Mannich bases remarkably increased the cytotoxicity in most cases. Quaternization procedure also improved the bioactivity in mono derivatives against Jurkat cells. Bis mannich bases 5-7 were found to be more active than 5-fluorouracil (6-23 fold) and melphalan (1.25-5 fold) against Renca cells. Except 2 and 8, the compounds synthesised were found to be more active than 5-fluorouracil (1.2-33 fold) against Jurkat cells.
