Cytotoxicity of 4-substituted quinoline derivatives: Anticancer and antileishmanial potential |
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| Affiliation: | 1. Laboratory of Heterocyclic Organic Chemistry, Department of Chemistry, Faculty of Sciences, Mohamed V University, BP1014, Rabat 10100, Morocco;2. Sorgun Vocational School, Science and Art Faculty-Department of Physics, Yozgat Bozok University, Yozgat, Turkey;3. Laboratory of Analytical Chemistry and Bromatology, Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Morocco;4. Department of Chemistry, Biochemistry, Molecular and Structural Biology Section, KULeuven, Celestijnenlaan 200F, Leuven 3001, Belgium;5. Moroccan Foundation for Advanced Science, Innovation and Research (Mascir), Department of Nanotechnology, Rabat Design Center, Rue Mohamed Al Jazouli Madinat Al Irfane Rabat 10 100, Morocco;6. Laboratoire de Biologie des Pathologies Humaines, Faculté des Sciences, Université Mohammed V, Rabat, Morocco |
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| Abstract: | Chemical modifications of quinoline moiety have been recognized as a useful strategy to development of new drugs. Here, the cytotoxicity of a set of twenty-four 4-substituted quinolines (named HTI) was screened for their antitumor and antileishmanial potential in vitro, and the underlying mechanisms investigated. HTI 21 and HTI 22 exhibited the highest cytotoxicity, being selected to the subsequent studies. Both derivatives induced caspase-dependent apoptosis associated to the dissipation of the mitochondrial transmembrane potential (ΔΨ) and ROS generation. HTI-induced cell death was calcium dependent, associated to thiol oxidation and cysteine proteases activation. In isolated mitochondria, HTI derivatives promoted mitochondrial permeabilization by different mechanisms. The inhibition of BCL-2 by venetoclax enhanced the HTI-induced cytotoxicity. Regarding the inhibition of cysteine proteases type B of Leishmania mexicana, HTI 15 exhibited the most potent inhibitory activity through a linear non-competitive mechanism. These data highlight the therapeutic potential of 4-substituted quinolines as antitumor and antileishmanial drugs. |
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| Keywords: | Antileishmanial Apoptosis Cancer Cysteine proteases Mitochondrial permeabilization Quinoline |
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