4-Hydroxyquinoline-3-carboxylic acids as inhibitors of cell respiration. 2. Quantitative structure-activity relationship of dehydrogenase enzyme and Ehrlich ascites tumor cell inhibitions

Abstract

Studies on dehydrogenase enzyme inhibition have been extended with the design, synthesis, and correlation analysis of 7-[(substituted-benzyl)oxy]-, 7-[(substituted-phenethyl)oxy]-, and 7([substituted-phenoxy)ethoxy]-4-hydroxyquinoline-3-carboxylic acids. Sixteen new congeners and the fifteen molecules previously synthesized have been tested against cytoplasmic malate dehydrogenase and lactate dehydrogenase, as well as against mitochondrial malate dehydrogenase. The lipophilic congeners show a clear specificity for inhibition of the mitochondrial enzyme. Correlation analysis of the data on the three enzymes allows a comparison of the binding sites in quantitative terms, while examination of the data on inhibition of ascites tumor cell respiration affords an indication of membrane transport. A newly developed high-pressure liquid chromatography based retention index is compared to the octanol-water pi constant as a model for hydrophobic interactions.

Analysis of Binding Energetics in Paper and Thin‐Layer Chromatography

“…As MR and log P are colinear for many of the common lipophilic sub-stituents, it requires thoughtful design to see the effect clearly. Inhibition of several dehydrogenases by 4-hydroxyquinoline-3-carboxylic acids as reported by Coats is the clearest example where inhibition correlates best with MR [9]. In this case, close approach of the variable substituent group is effected by strong hydrogen-bonding of the hydroxy and carboxylic groups.…”

Quantitative Structure-Activity Relationship Studies on Anticancer Drugs

“…[16][17][18][19] The selective inhibition of these enzymes in abnormal cells may lead to the inhibition of cellular respiration, resulting in the death of the cells. Certain copper(II) chelates20,21 and derivatives of 4-hydroxyquinoline-3-carboxylic acids22, 23 found to have direct effect on the inhibition of cellular respiration.…”

“…Even for a large series of nitrosoureas, the activity against L1210 leukemia was shown to be correlated with log P (eq 23). 60 In eq 23, the indicator variable 7i was used with a value of 1 for compounds where R substituent in the series VII had COOEt, CH3, or COOH group at its a-position, and 72 = 1 was used for the compounds The lipophilicity of substituents was also found to be the dominant determinant of anticancer activity in case of a large series of AT-aryl-iV'-(arylsulfonyl)ureas (VIII).61 In a cluster significance analysis of n = 90, r = 0.868, s = 0.206, log P0 = -4.4 (23) where this substituent had oxidizable S (not SO2) in the ring. The variable I3 was used for X substituent in the series VII.…”

“…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)…”

“…combined group (all compounds) log(l/C) = 10.1 + 6.59F1/2 + 0.35 logP n = 30, r =-0.83, s = 0.46, F227 = 30.3 (57) In these equations C was the average of in vitro assays (IC50) against three different human tumor cell lines, WiDr colon, 2780 ovarian, and MCF-7 breast cancer. For a comparative QSAR study, these authors however also evaluated the activity of these compounds against P388 leukemia in culture91 and performed the regression analysis to obtain the log(l/C) = 13.3 + 14.4E1/2 n = 16, r -0.91, s = 0.36, F1 >14 = 63.7 (58) mitomycin A analogues (compounds [20][21][22][23][24][25][26][27][28][29][30] log(l/C) = 8.88 + 0.32 log P n = 11, r = 0.62, s = 0.55, F19 = 5.52 (59) combined group (all compounds) log(l/C) = 10.84 + 8.63£1/2 + 0.32 logP n = 27, r = 0.87, s = 0.46, F2 24 = 36.2 (60)…”