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.
Highlights
During the biotransformation processes, drugs and chemicals are structurally modified by various enzymatic systems to form more polar substances, which can be excreted more than the original compounds
The metabolic degradation of compounds 2–4 was studied in the Cunninghamella biotransformation assay, being these derivatives tested in three different Cunninghamella species: C. echinulata, C. blakesleeana, and C. elegans
Compound 1 was not evaluated within this experiment due to its structural similarity to compound 2
Summary
Drugs and chemicals are structurally modified by various enzymatic systems to form more polar substances, which can be excreted more than the original compounds Problems arise when these modifications generate toxic products [1, 2]. Drug metabolism studies use in vivo experiments in mice, rat or guinea pig, or chimeric mouse models with transplanted human hepatocytes [3, 4] These models can create ethical dilemmas; and the experiments are expensive and time consuming [3]. Cunninghamella fungi can be used as an alternative to in vivo metabolism models [1,2,3, 5,6,7,8] The use of these microorganisms enables the reduction of research costs and does not arise ethical dilemmas. The fungus possesses the ability to metabolize a wide variety of xenobiotics in regio- and stereo-selective manners [9]
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