Comparative analysis of the cytotoxicity of substituted [phenylglyoxal bis(4-methyl-3-thiosemicarbazone]copper(II) chelates

Abstract

Seven para-substituted [phenylglyoxal bis(4-methyl-3-thiosemicarbazone)]copper (II) chelates (12-18) have been designed, synthesized, and tested for their ability to inhibit the respiration of rat liver slices as a normal cell model and Ehrlich ascites cells as a tumor cell model. Relationships between chemical structure and respiratory inhibition are described on a quantitative basis using substituent contants (pi, Es, and sigmap) by computerized multiparameter regression analyses. The correlations indicate that changes in Es have the largest effect on liver slice toxicity of chelates while pi and sigmap account for most of the variation in toxicity to ascites cells. A comparative analysis strongly suggests that electron-donating substituents with greater water solubility should increase cytotoxicity to ascites cells at the expense of cytotoxicity to the rat liver cells. The predictions of the equations were checked by synthesizing and testing an additional derivative. The results strengthen the initial predictions.

Role of chelates in treatment of cancer

“…Quantitative comparative analysis suggests that this selective action against the tumor cell system can be improved by substitution with groups having electron withdrawing and lipophilic nature. [30] 2. Beta-thujaplicin metal chelates act as promising anticancer agents.…”

“…Electron-donating substituent enhanced the water solubility resulting in increased cytotoxicity. [13] 2. Anticarcinogenic activity of copper di-Schiff bases (two novel di-Schiff bases coordinated with active center analogs of Cu 2 Zn 2 superoxide dismutase) effectively catalyzes the production of hydroxyl radicals in the presence and absence of TPA-activated polymorphonuclear leukocytes, thus leading to reduction in tumor size, delay of metastasis and a significant increase in survival of the hosts.…”

Quantitative Structure-Activity Relationship Studies on Anticancer Drugs

“…mitomycin C analogues (compounds [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] log(l/C) = 11.50 + 9.45F1/2 n = 19, r = 0.73, s = 0.48, Fu? = 19.4 (55) mitomycin A (R = CH30) analogues (compounds [20][21][22][23][24][25][26][27][28][29][30] log(l/C) = 8.58 + 0.44 logP n = 11, r = 0.80, s = 0.46, F1>9 = 15.9 (56)…”

“…A series of nitrogen mustards of isatins (VI) was CH2N(CH2CH2CI)2 VI synthesized and studied for their HeLa cell growth inhibition activity by Maysinger et al 54 These authors attempted to correlate this activity with log P and obtained eq 20 neglecting three compounds where Ri = N02. This exclusion and consequently obtaining a parabolic correlation based on only seven data points do not allow much confidence to be placed in eq 20. log(l/IC50) = 3.154 + 1.162 logP -0.256(logP)2 (20) n = 13, r = 0.904, s = 0.199, log P0 = 0.31 (22) 2. Nitrosoureas Nitrosoureas (VII) constitute another important class of alkylating agents possessing a variety of biologically significant effects.…”

Comparative analysis of the cytotoxicity of substituted [phenylglyoxal bis(4-methyl-3-thiosemicarbazone)]copper(II) chelates. 2. Parabolic correlations and their implications for selective toxicity

“…Equation 6 is given to allow comparison with eq 2 from the first stage of this work. 6 The parabolic relationship, eq 7, is now the most significant two-parameter equation and is an improvement over the linear relationship in alone (FU2 = 5.78; / , 2; = . 5 = 4.75).…”