title: Metabolism evaluation of the anticancer candidate AC04 by biomimetic oxidative model and rat liver microsomes.
abstract: Jacobsen reagents, in the presence of monooxygen donors, appear as an alternative to produce metabolites from biological active compounds. This reaction may mimic the oxidation and oxygenation reactions of cytochrome P450 (CYP450) enzymes upon various drugs and biologically active compounds. Acridines represent a well-known group of polyaromatic compounds capable of acting as DNA intercalating agents. Viewing to search for new anticancer agents, one promising new acridine, the 5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione (AC04) (2), has been studied by our group and the in vitro metabolism was investigated in this work, aiming to advance in the pre-clinical pharmacokinetic investigation. A systematic investigation of the gas-phase reaction, supported by computational chemistry, of the AC04 (2) was studied to help the structure elucidation of possible in vivo metabolites. To confirm the methodology, the oxidized product was obtained in large scale for NMR analysis and the data confirmed the structure. In addition, AC04 (2) was submitted to an in vitro metabolism assay employing rat liver microsomes and also, a pilot study was conducted in rats after AC04 intravenous (i.v.) dosing of 1.5 mg/kg. A single oxidized product was obtained from microsomal metabolism and detected in rat plasma by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis corresponding to the same product formed by Jacobsen-catalyzed reaction. These results indicate that Jacobsen oxidation reactions, combined with in vitro metabolism assays employing isolated microsomes, might replace some in vivo metabolism studies, thus reducing the use of animals in new chemical entities pre-clinical investigation.
authors: Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, Universidade Federal do Rio Grande do Sul, RS 90.610-000, Brazil.
authors: Maiara Cássia
authors: MC
authors: Pigatto
authors: Maria do Carmo
authors: Mdo C
authors: Alves de Lima
authors: Suely Lins
authors: SL
authors: Galdino
authors: Ivan da Rocha
authors: Ida R
authors: Pitta
authors: Ricardo
authors: R
authors: Vessecchi
authors: Marilda das Dores
authors: Md
authors: Assis
authors: Joicy Santamalvina
authors: JS
authors: dos Santos
authors: Teresa
authors: T
authors: Dalla Costa
authors: Norberto Peporine
authors: NP
authors: Lopes
mesh_terms: D000166:Acridines / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D032701:Biomimetics; D002855:Chromatography, Thin Layer; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D010865:Pilot Projects; D051381:Rats; D017208:Rats, Wistar; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D045162:Thiazolidinediones / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C568945:5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione; D000166:Acridines; D000970:Antineoplastic Agents; D045162:Thiazolidinediones