Nuran Diril

Some benzoxazoles and benzimidazoles as DNA topoisomerase I and II inhibitors.

Some novel fused heterocyclic compounds of 2, 5-disubstituted-benzoxazole and benzimidazole derivatives, which were previously synthesized by our group, were investigated for their inhibitory activity on both eukaryotic DNA topoisomerase I and II in a cell free system. 2-Phenoxymethylbenzimidazole (17), 5-amino-2-(p-fluorophenyl)benzoxazole (3), 5-amino-2-(p-bromophenyl)benzoxazole (5), 5-nitro-2-phenoxymethyl-benzimidazole (18), 2-(p-chlorobenzyl)benzoxazole (10) and 5-amino-2-phenylbenzoxazole (2) were found to be more potent as eukaryotic DNA topoisomerase I poisons than the reference drug camptothecin having IC50 values of 14.1, 132.3, 134.1, 248, 443.5, and 495 μM, respectively. 5-Chloro-2-(p-methylphenyl)benzoxazole (4), 2-(p-nitrobenzyl)benzoxazole (6) and 5-nitro-2-(p-nitrobenzyl)benzoxazole (8) exhibited significant activity as eukaryotic DNA topoisomerase II inhibitors, having IC50 values of 22.3, 17.4, 91.41 μM, respectively, showing higher potency than the reference drug etoposide.

A study on the genotoxic activities of some new benzoxazoles

The Bacillus subtilisrec assay has been specially developed to detect DNA-damaging potential in chemicals, with the rationale based on the relative difference of survival of a DNA repair combination proficient strains and its deficient strain, which is interpreted as genotoxicity. The genotoxic activities of newly (1–6) and previously (7–18) synthesized various benzoxazoles and benzimidazoles were analyzed via the B. subtilisrec assay. Newly obtained benzoxazole and benzimidazole derivatives (1–6) were synthesized in the presence of polyphosphoric acid (PPA) and 6 N HCl, respectively to detect their DNA-damaging activities. Among the tested compounds, 6-methyl-2-(o-chlorophenyl)benzoxazole (9), 5-amino-2-(p-methylbenzyl)benzoxazole (4), 5-(p-fluorobenzamido)-2-phenylbenzoxazole (13), and 2-(p-methylaminophenyl)benzoxazole (18) showed genotoxic activities having Rec50 values of 1.85, 1.74, 1.60, and 1.50 or S-probit values of 0.534, 0.482, 0.460, and 0.357, respectively. On the other hand, 2-(p-bromobenzyl)-5-methylbenzimidazole (6) and 2-benzyl-5-(p-fluorophenylacetamido)-benzoxazole (15) were exhibited a reverse effect that displayed a bacterial growth in the rec- strains while there was no any bacterial growth in rec+ strains at the same concentration.

Age-related activity of catalase in different genotypes of Drosophila melanogaster.

The enzyme catalase protects aerobic organisms from oxygen free radical damage by converting hydrogen peroxide to molecular oxygen and water before it can decompose to form the highly reactive hydroxyl radical. This damage has been implicated in the increased risk of disease and death associated with aging. In order to study the age-specific activity of catalase in male D. melanogaster, three different genotypes (Oregon w.t., ebony mutant, and the F1 hybrids of the two), whose mean life spans are about 55, 40, and 63 days, respectively, were used in the experiments. As the mean life span of the mutant is the shortest the enzyme activity was measured until the 43rd day, whereas in Oregon w.t., it continued until the 72nd day and in hybrids until the 79th day (longest-lived group). Although the enzyme activity in mutant flies increased sharply till the 9th day (and attained the highest level), later it declined sharply. In the other genotypes, the enzyme activity increased gradually until the 20-25th days, and then declined steadily in comparison to that of the ebony mutant. We found that higher catalase activity is associated with reduced life span for ebony mutant. It is obvious that some relationship exists between life span and antioxidant enzymes; however, a review of the literature does not at the moment allow as to understand the underlying mechanism involved in aging.

QSAR of genotoxic active benzazoles

Previously synthesized 2,5-disubstituted benzoxazole and benzimidazole derivatives, were tested for their genotoxic activity in the Bacillus subtilis rec− assay. The results revealed that 5-methyl-2-(p-aminobenzyl)benzoxazole exhibited the highest genotoxic response, which was comparable to 4-nitroquinoline 1-oxide (4-NQO), the reference agent of classical positive mutagen. Among the other tested compounds, four showed a genotoxic activity. A QSAR study revealed that structural parameters IYC2H4 and IYCH2O, indicating the bridge elements between the phenyl moiety and the fused ring system at position 2 and the quantum chemical parameter (ΔE ), showing the difference between HOMO and LUMO energies, were found significant for enhancing the genotoxic activity in these compounds. In addition, the substituent effects on positions R and R1 were found important for the activity as well as holding a substituent possessing a maximum length with a minimum width property on position R1 like alkyl groups. On the other hand, substituting position R with an electron donating group instead of electron withdrawing group increased the genotoxic activity. §Presented at the 12th International Workshop on Quantitative Structure-Activity Relationships in Environmental Toxicology (QSAR2006), 8–12 May 2006, Lyon, France.

Genotoxic potentials and eukaryotic DNA topoisomerase I inhibitory effects of some benzoxazine derivatives

Benzoxazines are heterocyclic compounds which have been used as intermediates in the synthesis of many heterocyclic structures of biological importance as it has been reported that some of the benzoxazines were effective in promoting apoptosis and inhibiting cell proliferation. Present study contains experimental data that showed genotoxic potentials and inhibitory effects on eukaryotic DNA topoisomerase I of 16 newly synthesized benzoxazine derivatives. By rec assay, the bacterial genotoxicity assay, only four tested compounds were found genotoxic at different concentrations and four compounds showed reverse effect. RC50 values evaluated by rec assay revealed that BS5 was the most genotoxic and BS4 was the most cytotoxic compound at micromolar concentration. Compounds were also tested for their inhibitory effects on eukaryotic DNA topoisomerase I enzyme and it was found that 14 of the compounds had inhibitory effects on eukaryotic DNA topoisomerase I enzyme. The most active compounds, BS18 and BS4, showed higher inhibitory activities than the positive control drug camptothecin which is a well-known commercial topoisomerase I inhibitor.

Biological evaluation and pharmacophore modeling of some benzoxazoles and their possible metabolites

A series of benzoxazole derivatives and some possible primary metabolites were evaluated as anticancer agents. In vitro anti‐proliferative activities of the compounds were tested using the SRB assay on cancerous (HeLa) and non‐cancerous (L929) cell lines. It was found that 17 of 21 tested compounds had cytotoxic activity on HeLa cells and the cytotoxic activities of the compounds were 15–700 times higher than on L929 cells. We generated two distinct pharmacophore models for the cytotoxic activities of the compounds on HeLa and L929 cells. While active compounds such as camptothecin and X8 fitted the two models generated for both cell lines, selective cytotoxic compounds such as XT3B fitted only the model generated for HeLa cells. Evaluation of the genotoxic activities of the cytotoxic compounds with the alkaline comet assay revealed that compounds X17 and XT3 showed strong genotoxic effects against HeLa cells at low concentrations whereas they had no genotoxic effect on L929 cells. Due to the selective ability for inducing DNA strand breaks only on cancerous cells, the compounds were identified as effective derivatives for anticancer candidates.