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

• Published in: Journal of medicinal chemistry 1982-01, Vol.25 (1), p.57-63
• Main Authors: Coats, Eugene A, Shah, Kishorkant J, Milstein, Stanley R, Genther, Clara S, Nene, Dilip M, Roesener, Jeffrey, Schmidt, James, Pleiss, Michael, Wagner, Ellen, Baker, John K
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Carcinoma, Ehrlich Tumor - drug therapy; Carcinoma, Ehrlich Tumor - metabolism; Hydroxyquinolines - pharmacology; L-Lactate Dehydrogenase - antagonists & inhibitors; Malate Dehydrogenase - antagonists & inhibitors; Oxygen Consumption - drug effects; Rabbits; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00343a011

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.