Erdem Buyukbingol

Recent studies of aldose reductase enzyme inhibition for diabetic complications.

Aldose reductase [ALR2; EC 1.1.1.21], a key enzyme of polyol pathway, catalyzes NADPH-dependent reduction of glucose to sorbitol (Sorbitol pathway), and an excessive accumulation of intracellular sorbitol found in various tissues of diabetic animals and in cells cultured under high glucose conditions has been proposed to be an important factor for the pathogenesis of diabetic complications. The only strategy shown to be consistently beneficial in the treatment of diabetic complications is meticulous control of blood glucose. However, aldose reductase (AR) enzyme inhibition is becoming one of the therapeutic strategies that have been proposed to prevent or ameliorate long-term diabetic complications. Therefore, AR inhibitors (ARIs) hold promise for reducing metabolic nerve injury, but further study is needed. On the other hand, there is strong evidence to show that diabetes is associated with increased oxidative stress. However, the source of this oxidative stress remains unclear. This relationship between diabetic complications and free radical production was also under investigation. The studies suggest that hydroxyl radical is indirectly inhibited by ARIs resulting from decreasing polyol levels and hydroxyl radical formation is related to the early stages of diabetic complications, possibly via the Fenton reaction involving H(2)O(2) produced from the activated polyol pathway. Therefore, it is proposed that hydroxyl radical may accelerate damage to the cell membranes resulting from polyol accumulation. The search for specific inhibitors of AR enzyme has still become a major pharmaceutic challenge, though a number of AR inhibitors have so far been assessed for diabetic complications.

A study on the antioxidant capacities of some benzimidazoles in rat tissues

Seven benzimidazole compounds were synthesized and their in vitro effects on rat liver, lung and kidney microsomal NADPH-dependent lipid peroxidation (LP) levels were determined. The significant decrease in male rat liver microsomal LP level was noted only by the compound 4 at 10(-4) M (20%) and 10(-3) M (40%) concentrations whereas the other compounds were ineffective. In lung, only the compound 6 at 10(-4) M concentration exhibited significant alteration, i.e. 56% increase, in LP level. In kidney, however, apart from the compound 4, all the compounds increased LP level (35-52%) significantly. The classical antioxidant, butylated hydroxy toluene (BHT), at 10(-4) M concentration, significantly decreased LP level about 70%, in all the tissues studied. To clarify the effects of compounds 4 and 6 on LP, the responses of some CYPs, which are active in producing reactive oxygen species, to these compounds were also investigated. The compound 4 at 10(-4) and 10(-3) M concentrations inhibited the hepatic microsomal ethoxyresorufin O-deethylase (EROD) (37 and 65%) and pentoxyresorufin O-depenthylase (PROD) (14 and 62%) enzyme activities significantly. However, it did not alter the hepatic microsomal NADPH-cytochrome P450-reductase activity. BHT, at 10(-3) M concentration, significantly inhibited hepatic microsomal EROD (73%), PROD (62%) and NADPH-cytochrome P450 reductase (17%) enzyme activities. Caffeine (10(-3)M) and SKF 525A (10(-3)M), which are specific inhibitors of EROD and PROD enzyme activities, significantly decreased the enzyme activities 33 and 77%, respectively. Caffeine was unable to alter hepatic microsomal NADPH-cytochrome P450 reductase enzyme activity whereas SKF 525A significantly inhibited (80%) it. In lung and kidney, the compound 6 at 10(-4)M concentration significantly increased EROD (44 and 19%) and PROD (103 and 86%) enzyme activities. However, the elevation of PROD enzyme activity in both tissues was observed to be more pronounced than that of EROD enzyme activity. This compound was ineffective on lung and kidney microsomal P450-reductase enzyme activity. These results reveal that the synthesized benzimidazoles have variable tissue dependent in vitro effects on LP due to their distinct effects on CYP activities but not on NADPH-cytochrome P450 reductase activity in rats.

Electroanalytical evaluation and determination of 5-(3'-indolyl)-2-thiohydantoin derivatives by voltammetric studies: possible relevance to in vitro metabolism

Some biologically important indolylthiohydantoin derivatives were investigated electroanalytically by voltammetric determination. Based on this study, a simple, rapid, sensitive and validated voltammetric method was developed for the determination of the indolylthiohydantoin derivatives that are readily oxidized at carbon-based electrodes. Due to the similarity between electrochemical and biological reactions it can be assumed that the oxidation mechanisms taking place at the electrode and in the body share similar principles. The oxidative behavior of the indole derivatives was studied as a function of pH at a glassy carbon electrode in different buffer media. The characteristics of the corresponding electrode reaction were discussed. The studied molecules are extensively metabolized in vivo, mainly through oxidative processes and we assume that the oxidation of the indolic compounds occurs on the nitrogen atom in the indole ring of the molecule. A linear response was obtained in the different media for all the compounds with a detection limit of 1.96 × 10−6 M, 2.32 × 10−6 M, 1.44 × 10−6 M and 7.10 × 10−7 M for compounds 1, 2, 3 and 4 respectively.

Antimicrobial activities of some tetrahydronaphthalene-benzimidazole derivatives.

Novel retinoid derivatives containing a benzimidazole moiety were synthesized and tested for their antimicrobial activity. Their antimicrobial activities against methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Candida krusei and Candida albicans were evaluated. While some of the compounds exhibited moderate activity against MRSA, S. aureus, E. faecalis, C. krusei and C. albicans, none of the compounds showed activity against E. coli and P. aeruginosa.

Synthesis and evaluation of in vitro antioxidant capacities of some benzimidazole derivatives

New, except 1d, melatonin analogue benzimidazole derivatives were synthesized and characterized in the present study. The potential role of melatonin as an antioxidant by scavenging and detoxifying ROS raised the possibility that compounds that are analogous to melatonin can also be used for their antioxidant properties. Therefore the antioxidant effects of the newly synthesized compounds were investigated in vitro by means of their inhibitory effect on hydrogen peroxide-induced erythrocyte membrane lipid peroxidation (EMLP) and on various erythrocyte antioxidant enzymes viz. superoxide dismutase (SOD), catalase (CAT) and glucose-6-phosphate dehydrogenase (G6PD). The synthesized benzimidazole derivatives showed remarkable antioxidant activity in vitro in the H2O2-induced EMLP system. Furthermore their effects on various antioxidant enzymes are discussed and evaluated from the perspective of structure- activity relationships.

Synthesis, anticancer activities and molecular modeling studies of novel indole retinoid derivatives

In this study, novel (E)-3-(5-substituted-1H-indol-3-yl)-1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)prop-2-en-1-one (5(a-e)) derivatives were synthesized and their anticancer effects were determined in vitro. Novel indole retinoid compounds except 5e have anti-proliferative capacity in liver, breast and colon cancer cell lines. This anti-proliferative effect was further analyzed in breast cancer cell line panel by using the most potent compound 5a. It was determined that 5a can inhibit proliferation at very low IC(50) concentrations in all of the breast cancer cell lines. Here, we present some evidence on apoptotic termination of cancer cell proliferation which may be primarily driven by the inhibition of RXRα and, to a lesser extent, RXRγ.

Synthesis of some novel oxime ether derivatives and their activity in the 'behavioral despair test'

Abstract In this study, a new series of 2-aminoethyloxime ether derivatives of some aralkylketones was synthesized. Their structures have been elucidated by UV, IR, 1 H-NMR, 13 C-NMR, mass spectra and elementary analysis. These compounds were then screened for their inhibition of immobility as an indicator of possible antidepressant activities by using the ‘behavioral despair test’. Results showed that all the new compounds decreased the immobility time, however, the inhibition observed with AO3 , AO4 and HO1 was significantly higher compared to fluvoxamine ( p

Effects of 2-arylbenzimidazoles on rat hepatic microsomal monooxygenase system.

1. The effects of eight newly synthesized 2-aryl substituted benzimidazole derivatives on control and phenobarbital (PB) treated rat liver microsomal aniline 4-hydroxylase and ethylmorphine N-demethylase activities, and their binding to control and PB-treated rat liver microsomal oxidized cytochrome P-450 are presented. 2. All compounds inhibited ethylmorphine N-demethylase activity with I50 values ranging from 8.50 x 10(-4) M to 27.83 x 10(-4) M in control and ranging from 2.80 x 10(-4) M to 15.79 x 10(-4) M in PB-treated rats. 3. Aniline 4-hydroxylase activity was inhibited by all of the compounds tested having I50 values in the range of 7.04 x 10(-4) M-31.37 x 10(-4) M in PB-treated rats, but only five of the compounds showed inhibitory activity in control rats. 4. Only a few significant regression coefficients could be found between the parameters of the chemicals studied and their inhibitory patterns. 5. No correlation has been observed between the binding of the derivatives and their inhibitory pattern.

Synthesis and effects of some novel tetrahydronaphthalene derivatives on proliferation and nitric oxide production in lipopolysaccharide activated Raw 264.7 macrophages.

In this study, novel N-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene-2-yl)-carboxamide (6-15) and 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide (16-32) derivatives were synthesized and their in vitro effects at 5 μM and 50 μM concentrations on proliferation and nitric oxide (NO*) production in lipopolysaccharide (LPS) activated RAW 264.7 macrophage cells were determined. Compounds 12, 17, 24 and 26 were found to decrease nitrite levels in a dose-dependent manner in LPS-activated cells. At the tested concentrations, these compounds did not exhibit cytotoxic effects. Interestingly, compound 27 which contains nitroxide free radical was the most active compound in this series showing 59.2% nitrite inhibition in LPS-activated macrophage cells.

A new proposed model of aldose reductase enzyme inhibition on the basis of an artificial intelligence approach: A computer automated structure evaluation (case) study

A large number of inhibitors of aldose reductase enzyme were submitted to the CASE (computer automated structure evaluation) program in order to ascertain the topological features relevant to activity. On the basis of the twenty-six biophores (activating fragments) and one biophobe (inactivating fragment), a new proposed interaction model was suggested for an aldose reductase enzyme with the chemical inhibitors. The critical relationship between enzyme inhibition and the structure of inhibitors is believed to depend on the relative positions of subordinate regions within the inhibitor structure.