Antioxidative or prooxidative effect of 4-hydroxyquinoline derivatives on free-radical-initiated hemolysis of erythrocytes is due to its distributive status.
7-Chloro-4-hydroxyquinoline (CQ) is an antitumor drug but its efficiency is not very satisfactory. This fact motivates us to study the relationship between the structure of 4-hydroxyquinoline with various substituent and its antioxidant effect against free-radical-initiated peroxidation: the hemolysis of human erythrocyte initiated thermally by water-soluble initiator, 2,2'-azobis (2-amidinopropane hydrochloride) (AAPH), acts as an experimental system. 7-Fluoro-4-hydroxyquinoline (FQ) and CQ can be synthesized by decarboxylation of 7-fluoro-4-hydroxyquinoline-3-carboxylic acid (FQCA) and 7-chloro-4-hydroxyquinoline-3-carboxylic acid (CQCA), respectively, and FQCA and CQCA are prepared by hydrolysis of ethyl 7-fluoro-4-hydroxyquinoline-3-carboxylate (FQCE) and ethyl 7-chloro-4-hydroxyquinoline-3-carboxylate (CQCE), respectively. The inhibitory concentration of 50% inhibition (IC(50)) of AAPH-induced hemolysis of the erythrocyte has been studied and found that all these chemicals dissolved in dimethyl sulfoxide (DMSO) can inhibit the free-radical-induced peroxidation. To clarify the relationship between the distributive status of the chemicals and their antioxidant effect, the chemical has been dissolved in the vesicle of dipalmitoyl phosphatidylcholine (DPPC) by sonication and suspended in the reaction system. It is found that FQCE, CQCE, FQCA and CQCA act as prooxidants either used alone or used in combination with alpha-tocopherol (TOH), demonstrating that FQCE, CQCE, FQCA and CQCA play a prooxidative role when they are packaged in the DPPC vesicle. This can be understood that the electron-attracting group, i.e. -COOC(2)H(5), -COOH, at the ortho position to the hydroxy group of quinoline makes the phenoxy radical of quinoline derivatives active by attracting negative charge from the electron-deficient radical site. These unstable free radicals preserved in DPPC vesicle can initiate additional propagation of lipid peroxidation and cause hemolysis. However, FQ and CQ without electron-attracting group are antioxidants even in DPPC vesicle either used alone, or mixed with TOH. Moreover, the antioxidative activity of FQ is much better than CQ either used alone or in combination with TOH, indicating that FQ has the potential to replace CQ to be an antioxidant drug. Therefore, the antioxidant/prooxidant effect is not only correlated with the molecular structure but also the distributive status in the reaction system.
Liu
Zai-Qun
ZQ
Department of Chemistry, Jilin University, Changchun 130023, PR China. zaiqun-liu@mail.jlu.edu.cn
Han
Kun
K
Lin
Ying-Jie
YJ
Luo
Xu-Yang
XY
D015060:1,2-Dipalmitoylphosphatidylcholine; D000578:Amidines; D000975:Antioxidants / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects*; D005609:Free Radicals / Q000037:antagonists & inhibitors; D006461:Hemolysis / Q000187:drug effects*; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D016877:Oxidants / Q000494:pharmacology; D013997:Time Factors; D024502:alpha-Tocopherol / Q000494:pharmacology
D000578:Amidines; D000975:Antioxidants; D005609:Free Radicals; D006912:Hydroxyquinolines; D016877:Oxidants; D015060:1,2-Dipalmitoylphosphatidylcholine; C046728:2,2'-azobis(2-amidinopropane); D024502:alpha-Tocopherol; C034010:4-hydroxyquinoline