Synthesis, In Vitro Cytotoxicity and Bleomycin‐Dependent DNA Damage Evaluation of Some Heterocyclic‐Fused Pyrimidinone Derivatives

Abstract

In this work, enaminones 1 a,b were used as precursors for the synthesis of novel fused heterocyclic ring systems (e. g. pyrazolo [3,4-d]pyrimidinones, isoxazolo[5,4-d]pyrimidinones, pyrimido [4,5-d]pyrimidinones and related compounds) via their reactions with some N-nucleophiles. The cytotoxic activity of the designed products was assessed via the MTT colorimetric assay against human liver hepatocellular carcinoma (HepG2) and normal lung fibroblasts (WI-38) cell lines using doxorubicin as a reference standard. Among the screened compounds, pyrazolo[3,4-d]pyrimidinone 3 d and pyrimido [4,5-d] pyrimidinones 6 a,b, 7 b and 8 a,b were selected as lead molecules because they showed significant activity against HepG2 cells and a weak cytotoxic effect against WI-38 cells. In further, all of the compounds were subjected to the bleomycin-dependent DNA damage studies. The results indicated that most of them have a remarkable ability to protect DNA compared to ascorbic acid as a standard compound.

Investigation of the Inhibition Mechanism of Xanthine Oxidoreductase by Oxipurinol: A Computational Study

“…Like xanthine, oxipurinol can exist as a mixture of tautomers (see Figure S15). Several reports on the chemical synthesis of oxipurinol have demonstrated that tautomer-1 represents the predominant tautomeric form of this compound. ,− In vitro and in vivo studies have also suggested that tautomer-1 is the functional derivative of oxipurinol with biological activity. − Moreover, Truglio et al suggested that the N9 nitrogen of oxipurinol (see Scheme A, middle) in their XDH–oxipurinol-inhibited crystal structure from Rhodobacter capsulatus (PDB ID: 1JRP) presumably acts as NH and forms a hydrogen bond to E730 (identical to E1261 in bovine XO). Hernández et al computationally showed that among the probable tautomers of oxipurinol, shown in Figure S15, di-keto tautomers (tautomers 1 and 2) are favorable in the gas phase and aqueous solution.…”

Computational Insights into the Inhibition Mechanism of Xanthine Oxidoreductase by Oxipurinol

“…Several reports on the chemical synthesis of oxipurinol have demonstrated that tautomer-1 represents the predominant tautomeric form of this compound. 49,[189][190][191][192][193][194] In vitro and in vivo studies have also suggested that tautomer-1 is the functional derivative of oxipurinol with biological activity. [195][196][197][198][199][200] Moreover, Truglio et al 48 suggested that the N9 nitrogen of oxipurinol (see Scheme 1C left) in their XDH-oxipurinol inhibited crystal structure from Rhodobacter capsulatus (PDB ID: 1JRP) is presumably as NH and forms a hydrogen bond to E730 (identical to E1261 in bovine XO).…”

Novel Furan and Furo[2,3–d]pyrimidinone Analogues: Cytotoxicity, Antioxidant, and Bleomycin‐Dependent DNA Damage Assessment

“…[14] Through the course of our earlier drug discovery work involving the synthesis of novel heterocyclic compounds, we found that pyrimidine heterocycles displayed cytotoxic activities against the variety of cancer cell lines, antioxidant, and protected cells from damage caused by bleomycin. [15,16] In light of the aforementioned facts, and given the immense biological potential associated with furan and furo [ 2,3-d]pyrimidine analogues, and in keeping with our interest in the synthesis of bioactive molecules, [17][18][19] it would be worthwhile to focus on the synthesis of these derivatives. Herein, we intend to explore efficient synthetic methodologies to synthesize novel furan, and furo [2,3-d]pyrimidine heterocycles with exceptional yields and high purity.…”

“…On the other hand, furo[2,3– d ]pyrimidines have been found to possess antimicrobial activity, [7] kinase inhibitors, [8] anticancer against lung tumor cell lines, [9] antifolates, [10] inhibitors of dihydrofolate reductases, [11] VEGFR2 dual inhibitors, [12] used as microtubule‐targeting compounds against tumour cells with drug resistance, [13] and demonstrated analgesic and antitumor activities [14] . Through the course of our earlier drug discovery work involving the synthesis of novel heterocyclic compounds, we found that pyrimidine heterocycles displayed cytotoxic activities against the variety of cancer cell lines, antioxidant, and protected cells from damage caused by bleomycin [15,16] . In light of the aforementioned facts, and given the immense biological potential associated with furan and furo [ 2,3– d ]pyrimidine analogues, and in keeping with our interest in the synthesis of bioactive molecules, [17–19] it would be worthwhile to focus on the synthesis of these derivatives.…”