Tülay Çoban

Synthesis and antioxidant properties of novel N-methyl-1,3,4-thiadiazol-2-amine and 4-methyl-2H-1,2,4-triazole-3(4H)-thione derivatives of benzimidazole class

Some novel 1-methyl-4-(2-(2-substitutedphenyl-1H-benzimidazol-1-yl)acetyl)thiosemicarbazides (16a-20a), 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl]-N-methyl-1,3,4-thiadiazol-2-amines (17b-20b), and 5-[(2-(substitutedphenyl)-1H-benzimidazol-1-yl)methyl-4-methyl-2H-1,2,4-triazole-3(4H)-thiones (16c-20c) were synthesized and tested for antioxidant properties by using various in vitro systems. Compounds 16a-20a were found to be a good scavenger of DPPH radical (IC(50), 26 microM; IC(50), 30 microM; IC(50), 43 microM; IC(50), 55 microM; IC(50), 74 microM, respectively) when compared to BHT (IC(50), 54 microM). Noteworthy results could not be found on superoxide radical. Compound 19b, which is the most active derivative inhibited slightly lipid peroxidation (28%) at 10(-3)M concentration. Compound 17c inhibited the microsomal ethoxyresorufin O-deethylase (EROD) activity with an IC(50)=4.5 x 10(-4)M which is similarly better than the specific inhibitor caffeine IC(50)=5.2 x 10(-4)M.

The expression of cytochrome P450 enzymes in human breast tumours and normal breast tissue

Environmental chemicals are one of the risk factors in breast cancer genesis. Cytochrome P450 (CYP) enzymes play a major role in the activation of these chemicals. Using highly specific and sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, the expression profile of all major xenobiotic metabolizing CYP forms was screened in breast tumour and surrounding tumour free (control) breast tissue in a series of 20 sample pairs obtained from females with infiltrating ductal carcinoma. The levels of CYP1A1 mRNA were very low in both tumour and normal tissue. CYP1B1, CYP2B6, CYP2C, CYP2D6, CYP2E1, CYP4B1, and CYP11A1 expressions were positive in both tumours and control tissue. CYP2A6, CYP2A7, CYP2A13, CYP2F1, CYP3A4, CYP3A5, and CYP3A7 mRNAs were expressed neither in tumours nor in control tissue. These results show that several CYPs, responsible for the activation of a quite large number of procarcinogens and genotoxic estrogen metabolites, are expressed in breast tissue with a lack of qualitative differences in CYP expression at mRNA level between breast tumours and surrounding normal breast.

Synthesis and Antioxidant Properties of Novel Benzimidazole Derivatives

Some novel benzimidazole derivatives carrying thiosemicarbazide and triazole moieties at the N1 position were synthesized and their in vitro effects on rat liver microsomal NADPH-dependent lipid peroxidation (LP) levels determined by measuring the formation of 2-thiobarbituric acid reactive substance. The free radical scavenging properties of the compounds were also examined in vitro by determining the capacity to scavenge superoxide anion formation and the interaction with the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). The compounds showed a significant effect in the above tests except to scavenge superoxide anion formation.

Investigation of the in vitro antioxidant behaviour of some 2-phenylindole derivatives: discussion on possible antioxidant mechanisms and comparison with melatonin

Oxidative stress has been implicated in the development of many neurodegenerative diseases and also responsible from aging and some cancer types. Indolic compounds are a broad family of substances present in microorganisms, plants and animals. They are mainly related to tryptophan metabolism, and present particular properties that depend on their respective chemical structures. Due to free radical scavenger and antioxidant properties of indolic derivatives such as indolinic nitroxides and melatonin, a series of 2-phenyl indole derivatives were prepared and their in vitro effects on rat liver lipid peroxidation levels, superoxide formation and DPPH stable radical scavenging activities were determined against melatonin, BHT and α-tocopherol. The compounds significantly inhibited (72–98%) lipid peroxidation at 10− 3 M. These values were similar to that observed with BHT (88%). Possible structure–activity relationships of the compounds were discussed.

The Organochlorine Pesticide Residues and Antioxidant Enzyme Activities in Human Breast Tumors: Is There Any Association?

The levels of some organochlorine pesticides (OCP)s (hexachlorobenzene, HCB, α-hexachlorocyclohexane, α-HCH, β-HCH, γ-HCH, heptachlorepoxide, HE, bis (4-chlorophenyl)-1,1-dichloroethene, p.p′DDE, bis (4-chlorophenyl)-1,1,1-trichloroethane, p.p′ DDT and total DDT (Σ-DDT) and antioxidant enzyme activities namely Cu, Zn superoxide dismutase (SOD), catalase (CAT), selenium-dependent glutathione peroxidase (Se-GSH-Px), total glutathione peroxidase (T-GSH-Px), selenium independent glutathione peroxidase (GSH-Px II), glutathione reductase (GRd), level of reduced glutathione (GSH) and lipid peroxidation (LP), glutathione S-transferase (GST) activity toward several substrates including 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EAA), 1,2-epoxy-3-(p-nitrophenoxy)-propane (ENPP) were measured in tumor and surrounding tumor free tissues of 24 female breast cancer patients and was evaluated whether there exist any association between the levels of OCPs and antioxidants. The mean levels of GSH, α-BHC, γ-BHC and HE, and activities of SOD, Se-GSH-Px, T-GSH-Px, GSH-Px II,GRd, GST CDNB, and GST DCNB were significantly higher in tumors than in controls. In tumors, significant correlations were noted between: SOD and γ-BHC; Se-GSH-Px and γ-BHC; T-GSH-Px and γ-BHC; GSH-Px II and α-BHC, γ-BHC; GSH and α-BHC, γ-BHC, HE; GRd and α-BHC; CDNB GST and α-BHC, γ-BHC. These results show that free-radical mediated oxidative stress is, at least partly, associated with some of these OCP residues in human breast tumors.

Melatonin analogue new indole hydrazide/hydrazone derivatives with antioxidant behavior: Synthesis and structure–activity relationships

Melatonin (MLT) is a hormone produced in the brain by the pineal gland, from the amino acid tryptophan. It is also an antioxidant hormone with a particular role in the protection of nuclear and mitochondrial DNA. In recent years, many physiological properties of MLT have been described resulting in much attention in the development of synthetic compounds possessing the indole ring. Sixteen MLT analogue indole hydrazide/hydrazone derivatives were synthesized and in vitro antioxidant activity was investigated. Most of the compounds showed significantly higher activity than MLT at 10− 3 M and 10− 4 M concentrations.

Synthesis and antioxidant properties of novel benzimidazoles containing substituted indole or 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene fragments

Some 6-fluoro-5-substituted-benzimidazole derivatives in which indole and 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene groups were attached to the 2-position of the benzimidazole ring were synthesized and tested for antioxidant properties in vitro. Almost all the synthesized compounds at the 10− 3 M concentrations showed superoxide anion scavenging activity. Compounds 5, 3, 9, 4, 17 and 13 have strong inhibitory effects on superoxide anion formation (98%, 93%, 91%, 88%, 85% and 81%, respectively) at 10− 3 M concentration and these results are better than 30 IU of superoxide dismutase (SOD) (76%). Compound 11 is the most effective scavenger of 2,2-diphenyl-1-picrylhydrazyl (DPPH) stable free radical at 10− 3 M (61%) concentration.

Antioxidant Activities of Plants Used in Traditional Medicine in Turkey

Ethanol extracts from 6 species representing six different families, used in traditional medicine in Turkey were evaluated for their antioxidant activities. The inhibition of superoxide anion formation and lipid peroxidation levels of Ononis spinosa, Centranthus longiflorus, Lythrum salicaria, Plantago major, Juglans regia and Teucrium polium extracts were tested using in vitro standard procedures and IC50 values were determined. In vitro tests included superoxide anion radical scavenging activity and lipid peroxidation. All ethanol extracts of plants showed concentration-dependent superoxide anion radical scavenging activity. The results of the superoxide anion formation assay showed that the ethanol extract of Centranthus longiflorus was found to be most potent inhibitor (IC50 0.77 mg/ml) and followed by Plantago major (IC50 1.21 mg/ml), Juglans regia (IC50 1.39 mg/ml), Ononis spinosa (IC50 1.35 mg/ml), Teucrium polium (IC50 3.10 mg/ml) and Lythrum salicaria (IC50 5.00 mg/ml). All the extracts, excluding Ononis spinosa and Teucrium polium, showed concentration-dependent inhibitory effect on lipid peroxidation. IC50 values of the effective ethanol extracts of plants on lipid peroxidation were as follows: Juglans regia (IC50 3.3 mg/ml), Plantago major (IC50 3.4 mg/ml), Centranthus longiflorus (IC50 3.9 mg/ml) and Lythrum salicaria (IC50 5.3 mg/ml). The results showed that Centranthus longiflorus, Plantago major and Juglans regia extracts had the highest antioxidant capacities among the six species examined.

Combined effects of cadmium and nickel on testicular xenobiotic metabolizing enzymes in rats

When male rats were given a single dose of cadmium (Cd) (3.58 mg CdCl2·H2O/kg, ip) 72 hr prior to sacrifice, the testicular 7-ethoxyresorufin O-deethylase (EROD) and glutathione S-transferase (GST) activities toward the substrates 1-chloro-2,4-dinitrobenzene (CDNB), 1,2-dichloro-4-nitrobenzene (DCNB), ethacrynic acid (EAA), 1,2-epoxy-3-(p-nitrophenoxy)-propane (EPNP), and cumene hydroperoxide (CHPx) decreased significantly as compared to controls. Cd also inhibited reduced glutathione (GSH) level while increasing the lipid peroxidation (LP) level significantly. When the animals were given a single dose of nickel (Ni) (59.5 mg NiCl2·6H2O/kg, ip) 16 hr prior to sacrifice, significant decreases were observed in EROD and GST activities toward CDNB, EAA, EPNP, and CHPx, and GSH level. No significant alterations were noted in DCNB GST activity and LP level by Ni. For the combined treatment, rats received the single dose of Ni 56 hr after the single dose of Cd and were killed 16 hr later. In these animals, lesser depressions were observed on EROD activity and LP level than those of Cd alone. The combination of metals significantly inhibited GST activities and GSH level but not to a greater degree than noted by Cd or Ni alone. Plasma testosterone levels of Cd-, Ni-, and combination-treated rats decreased significantly compared to controls. The strongest depression was achieved by Cd alone. Cd, both alone and in combination with Ni, increased the tissue Ni uptake significantly. Ni, however, did not produce such an effect on the tissue uptake of Cd in either case. Cd treatment caused interstitial edema and coagulation necrosis in seminiferous tubules and also caused fibrinoidal necrosis in vascular endothelium. Ni treatment did not produce any pathological testicular alterations compared to controls. Combined treatment produced fewer pathological alterations (i.e., only interstitial edema) than that of Cd treatment. These results reveal that the combination of Cd and Ni does not have a synergistic effect on testicular xenobiotic metabolizing enzymes, and in contrast, Ni has an ameliorating effect on pathological disturbances caused by Cd alone in the rat testis.

A Comparative Study: Evaluation of Antioxidant Activity of Melatonin and Some Indole Derivatives

To understand antioxidant activity and the role played by melatonin, we have designed and tested several new compounds. We present the results in terms of structure-activity relationships, focusing on the lack of the methoxy group and the influence of the amide side chain. Antioxidant activity of melatonin and some new melatonin analogue indole derivatives were investigated, using lipid peroxidation and superoxide anion radical scavenger activity assays, in rat liver tissue homogenate. Most of the compounds were found to be very potent inhibitors of malondialdehyde (MDA) formation at 10−3M. Inhibition rates ranged from 75-44 %. However, no significant inhibitory effect was obtained on superoxide anion formation. Consequently, it can be concluded that these compounds exhibit important LP activity compared to melatonin.