Cytotoxicity of Some Azines of Acetophenone Derived Mono-Mannich Bases against Jurkat Cells

Abstract

Mannich bases have several biological activities such as antimicrobial, [1][2][3][4][5] cytotoxic, [6][7][8][9] anticancer, 10) analgesic, 11) anti-inflammatory, 12,13) diuretic 14,15) and anticonvulsant [16][17][18][19] activities. An amino ketone, Mannich base, containing at least one activated hydrogen atom at the b position to an amino function, can undergo deamination in vivo 20) or under simulated in vitro conditions 1,3,6) to liberate the corressponding a,b-unsaturated ketones. The a,b-unsaturated ketone is an active center for nucleophilic attack. The biological activities of Mannich bases, such as antimicrobial, [1][2][3]21,22) cytotoxic and anticancer 6,9,23) activities, have been attributed to these liberated a,b-unsaturated ketones which can alkylate nucleophiles, especially thiol groups 1,6,24,25) rather than amino and hydroxyl groups, 26) by Michael type addition reactions of nucleophiles to a,b-unsaturated ketones.27) In addition, enzyme-catalyzed alkylation of the thiol group of cystein with a,b-unsaturated carbonyl compounds has been observed. 28)The antimicrobial activity of a,b-unsaturated ketones is due to their reactions with essential thiol groups in bacteria and fungi, resulting in b-ketothioethers.29) Electron densities on b-carbons are lower 30) than on a-carbons in various unsaturated ketones, and thus the attack of the nucleophils should occur at the b-carbon atoms. It was also shown that increased antimicrobial activity was associated with an increased breakdown of the Mannich bases.29) Similarly, a number of a,b-unsaturated ketones have alkylating ability against biologically important nucleophiles to produce cytotoxicity. 21,23) The amino group in Mannich bases would increase the water solubilizing property of the molecule, which may assist in transportation of the compound to the site of action.Production of thiol adducts in the stability studies, 1,3,6) carried out under in vitro physiological conditions (in phosphate buffer with pH 7.4, at 37°C), with 2-mercaptoethanol, various unsaturated ketones or Mannich bases, suggests that a,bunsaturated ketones and Mannich bases producing unsaturated ketones by deamination to exert their antimicrobial activities by thiol alkylation of unsaturated ketones.Clark and co-workers 31) found that the thiol adduct had the greatest fungitoxicity, which was probably due to the same reaction. Dimmock et al. (1994) have shown that Mannich bases of conjugated styryl ketones inhibit one or more of the following enzymes in the glutathione metabolic pathway: namely, glutathione S-transferases, glutathione reductase, gamma-glutamyl transpeptidase and glutathione peroxidase in Candida albicans. 32) They concluded that the antifungal activity of the Mannich bases of conjugated styryl ketones may be due, at least in part, to interference with the GSH metabolic pathway. In one of our previous studies, we observed that mono-Mannich bases and bis Mannich bases decrease the total glutathione level in a dose-dependent manner when Jurkat cells are exposed to the co...

Synthesis of 3-aroyl-4-aryl-1-isopropylamino-4-piperidinols and evaluation of the cytotoxicities of the compounds against human hepatoma and breast cancer cell lines

“…According to the studies carried out, the following activities of Mannich bases have been identified: anticancer 4 , cytotoxic [5][6][7][8][9][10][11][12][13] , anti-inflammatory [14][15][16] , anticonvulsant 17,18 and antifungal 19,20 . Their cytotoxic activities were attributed to the a,b-unsaturated ketone, which is available in the chemical structure of the compound or to the product produced by deamination process in vivo or under simulated conditions in vitro 7,21,22 .…”

Symmetrical Acyclic Aryl Aldazines with Antibacterial and Antifungal Activity

“…Ketazines, mixed azines, and cyclic compounds have exhibited antitumor [7][8][9][10][11][12], anti-bacterial [13][14][15][16][17][18][19][20], anti-inflammatory [21], antimalarial dyes [22], anticonvulsant [23,24], insect growth regulators [25] and many other activities. Contrary, acyclic aldazines are much less studied.…”

Synthesis and Cytotoxicity of Novel 3-Aryl-1-(3′-dibenzylaminomethyl-4′-hydroxyphenyl)-propenones and Related Compounds

“…[1][2][3][4][5][6] The bioactivity of Mannich ketones may be due to the alkylating ability of a,b-unsaturated ketones that are liberated in situ following deamination (Fig. 1).…”

“…1). 2,4,[7][8][9][10][11] Various studies on Mannich ketones have been reported from our laboratory [1][2][3][4][5][6] but toxicities 7,8) associated with this class of compounds have discouraged us to pursue them further. The unwanted toxicities associated with the Mannich ketones may be due to the rapid decomposition to form a reactive enone which is sequestered indiscriminately with cellular nucleophiles.…”