In Vitro Biotransformation, Safety, and Chemopreventive Action of Novel 8-Methoxy-Purine-2,6-Dione Derivatives

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.

Selenazolinium Salts as “Small Molecule Catalysts” with High Potency against ESKAPE Bacterial Pathogens

“…Each experiment was performed in triplicate, and results were given in terms of mutagenic index (MI), which is the quotient of the number of revertant colonies induced in a test sample and the number of revertants in a negative control (media with 1% DMSO). A compound is considered mutagenic if MI is above 2.0 [ 30 , 31 ]. According to the results obtained ( Figure 2 ), neither selenazolinium salts ( 1 – 8 ) nor ebselen appeared to cause any significant mutagenic changes at the concentrations used (1 µM and 10 µM), resulting in MI below 2.0, whereas the MI value for reference NQNO (0.5 μM) was 7.24 ( Table 5 ).…”

Pharmaceutical and Safety Profile Evaluation of Novel Selenocompounds with Noteworthy Anticancer Activity

“…Nevertheless, these standard assays are limited by ethical concerns, high costs, the toxicity of the administered drugs, and the small quantity of the isolated metabolites and specious variations. Consequently, there is now a tendency to replace these methods with modern, alternative in vitro methods, such as the use of liver microsomes, microorganisms (fungi), perfused organs, tissues, or cell cultures in biotransformation metabolic studies [29,44,67,68].…”

“…Thanks to these mutations, the excision repair mechanisms are deactivated and the bacteria become more permeable to chemicals, respectively. Lastly, TA100 also includes the pKM101 plasmid, which is used to enhance both chemical and UV-induced mutagenesis and to increases the error-prone recombinational DNA repair pathway [29][30][31]. This strain of Salmonella Typhimurium is not able to produce histidine.…”

Biotransformation of 4‐fluoro‐N‐(1‐{2‐[(propan‐2‐yl)phenoxy]ethyl}‐8‐azabicyclo[3.2.1]octan‐3‐yl)‐benzenesulfonamide, a novel potent 5‐HT7 receptor antagonist with antidepressant‐like and anxiolytic properties: In vitro and in silico approach

“…Additionally, various microbial systems employing bacteria, yeast, and fungi may constitute an alternative to the use of animal models in the study of NCEs metabolism . The zygomycete fungus Cunninghamella can perform both phase I and phase II biotransformation reactions and was shown to metabolize chemical compounds in a way similar to mammals …”

“…[7][8][9] The zygomycete fungus Cunninghamella can perform both phase I and phase II biotransformation reactions and was shown to metabolize chemical compounds in a way similar to mammals. [7,[10][11][12][13][14][15] Recently, a series of novel arylsulfonamide/amide derivatives of (aryloxy)ethyl alkyl amines was designed and synthesized in the Department of Medicinal Chemistry, Jagiellonian University Medical College. Subsequently, representative compounds affinity for 5-HT 7 receptors (Rs) and selectivity over related 5-HTRs (5-HT 1A Rs, 5-HT 2A Rs, 5-HT 6 Rs), dopamine D 2 Rs, and adrenergic 1 Rs was estimated.…”