Genotoxicity risk assessment of diversely substituted quinolines using the SOS chromotest

Abstract

Quinolines are aromatic nitrogen compounds with wide therapeutic potential to treat parasitic and microbial diseases. In this study, the genotoxicity of quinoline, 4-methylquinoline, 4-nitroquinoline-1-oxide (4-NQO), and diversely functionalized quinoline derivatives and the influence of the substituents (functional groups and/or atoms) on their genotoxicity were tested using the SOS chromotest. Quinoline derivatives that induce genotoxicity by the formation of an enamine epoxide structure did not induce the SOS response in Escherichia coli PQ37 cells, with the exception of 4-methylquinoline that was weakly genotoxic. The chemical nature of the substitution (C-5 to C-8: hydroxyl, nitro, methyl, isopropyl, chlorine, fluorine, and iodine atoms; C-2: phenyl and 3,4-methylenedioxyphenyl rings) of quinoline skeleton did not significantly modify compound genotoxicities; however, C-2 substitution with α-, β-, or γ-pyridinyl groups removed 4-methylquinoline genotoxicity. On the other hand, 4-NQO derivatives whose genotoxic mechanism involves reduction of the C-4 nitro group were strong inducers of the SOS response. Methyl and nitrophenyl substituents at C-2 of 4-NQO core affected the genotoxic potency of this molecule. The relevance of these results is discussed in relation to the potential use of the substituted quinolines. The work showed the sensitivity of SOS chromotest for studying structure-genotoxicity relationships and bioassay-guided quinoline synthesis.

Toluene Dioxygenase-Catalyzed cis-Dihydroxylation of Quinolines: A Molecular Docking Study and Chemoenzymatic Synthesis of Quinoline Arene Oxides

“…Identification of mammalian metabolites of quinoline 1 and their role in its mutagenicity and tumorigenicity, has been of interest for more than 40 years (Hollstein et al, 1978;Tada et al, 1980Tada et al, , 1982LaVoie et al, 1983;Agarwal et al, 1986Agarwal et al, , 1990Willems et al, 1992;Saeki et al, 1993;Reigh et al, 1996;Suzuki et al, 2000;Dowers et al, 2004;Hakura et al, 2007;Diaz Duran et al, 2015;Matsumoto et al, 2018). Several quinoline arene oxides, e.g., 20 and 27, were initially postulated as possible liver microsomal metabolites of quinoline 1 (Hollstein et al, 1978;Tada et al, 1980Tada et al, , 1982LaVoie et al, 1983), before 5,6-arene oxide 20 was finally confirmed as a major metabolite (Figure 8) (Agarwal et al, 1986).…”

“…Quinoline 1 is a mammalian hepatocarcinogen and a bacterial mutagen, with its metabolites binding covalently to DNA. Possible pathways responsible for these biological effects continue to be of interest (Hollstein et al, 1978;Tada et al, 1980Tada et al, , 1982LaVoie et al, 1983;Agarwal et al, 1986Agarwal et al, , 1990Willems et al, 1992;Saeki et al, 1993;Reigh et al, 1996;Suzuki et al, 2000;Dowers et al, 2004;Hakura et al, 2007;Diaz Duran et al, 2015;Matsumoto et al, 2018). Cytochrome P-450 (CYP-450) monooxygenases have been identified as responsible for catalyzing epoxidation and dearomatization of quinolines, during mammalian liver metabolism.…”