In Vitro Biotransformation, Safety, and Chemopreventive Action of Novel 8-Methoxy-Purine-2,6-Dione Derivatives
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In Vitro Biotransformation, Safety, and Chemopreventive Action of Novel 8-Methoxy-Purine-2,6-Dione Derivatives Małgorzata Anna Marć 1 & Enrique Domínguez-Álvarez 1,2 & Karolina Słoczyńska 1 & Paweł Żmudzki 3 & Grażyna Chłoń-Rzepa 3 & Elżbieta Pękala 1
Received: 6 April 2017 / Accepted: 29 May 2017 # The Author(s) 2017. This article is an open access publication
Abstract Metabolic stability, mutagenicity, antimutagenicity, and the ability to scavenge free radicals of four novel 8-methoxy-purine-2,6-dione derivatives (compounds 1–4) demonstrating analgesic and anti-inflammatory properties were determined. Metabolic stability was evaluated in Cunninghamella and microsomal models, mutagenic and antimutagenic properties were assessed using the Ames and the Vibrio harveyi tests, and free radical scavenging activity was evaluated with 2,2-diphenyl-1-picrylhydrazyl radical scavenging assay. In the Cunninghamella model, compound 2 did not undergo any biotransformation; whereas 3 and 4 showed less metabolic stability: 1–9 and 53– 88% of the parental compound, respectively, underwent biotransformation reactions in different Cunninghamella strains. The metabolites detected after the biotransformation of 3 and 4 were aromatic hydroxylation and N-dealkylation products. On the other hand, the N-dealkylation product was the only metabolite formed in microsome assay. Additionally, these derivatives do not possess mutagenic potential in microbiological models (Vibrio harveyi and Salmonella typhimurium) considered. Moreover, all compounds showed a strong chemopreventive activity in the modified Vibrio harveyi strains BB7X and BB7M. However, radical scavenging activity was not the mechanism which explained the observed chemopreventive activity.
* Elżbieta Pękala [email protected]
1
Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
2
Institute of General Organic Chemistry, Spanish National Research Council (IQOG-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
3
Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland
Appl Biochem Biotechnol
Keywords Alternative test . Ames test . Cunninghamella assay . DPPH assay . Microsomal stability
Introduction During the biotransformation processes, drugs and chemicals are structurally modified by various enzymatic systems to form more polar substances, which can be excreted more easily than the original compounds. Problems arise when these modifications generate toxic products [1, 2]. Traditionally, drug metabolism studies use in vivo experiments in mice, rat or guinea pig, or chimeric mouse models with transplanted human hepatocytes [3, 4]. However, these models can create ethical dilemmas; and the experiments are expensive and time consuming [3]. In addition, metabolites are sometimes produced in low amounts, thus hindering their identification [4]. Enzymatic systems involved in the metabolism of exo
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