Genotoxicity studies on benzimidazole retinoids.

Retinoids consist of a family of naturally occuring compounds including all-trans retinoic acid (ATRA), retinal, retinol (vitamin A), 9-cis retinoic acid, 13-cis retinoic acid as well as a large number of synthetic derivatives. Retinoids are known to elicit diverse pharmacological profiles such as controlling cell differentiation/proliferation and modulating specific premalignant lesions and reducing second primary tumors in patients. Clinical use of retinoids is limited due to their toxicity. Three benzimidazole retinoid derivatives (BITN, BITNm, BITNe) were synthesized and were examined in terms of genotoxicity towards human lymphocyte cultures by sister chromatid exchange (SCE) analysis. It has been found that BITN decreased the number of SCEs 20% at 10(-6) M, but had no effect at 10(-5) M. No significant effect on SCEs was observed for BITNm and BITNe at both concentrations. ATRA increased the SCEs (35%) at 10(-5) M but had no effect at 10(-6) M. The results have shown that benzimidazole retinoids did not induce SCE significantly. Besides this, BITN reduced the SCEs and had a protective effect at low concentration. Since the induction of glutathione S-transferase (GST) is associated with anticancer drug resistance, the effects of BITN, BITNm, BITNe and ATRA on human lymphocyte GSTs were also investigated using CDNB as substrate. BITN and BITNm induced GST activities 54% and 49% respectively at 10(-5) M, but had no effect at 10(-6) M. BITNe induced GST activity 62% at 10(-5) M and 35% at 10(-6) M. ATRA had no effect on GST activity at 10(-5) M.

Synthesis and antioxidant properties of some indole ethylamine derivatives as melatonin analogs.

The synthesis and lipid peroxidation (LP) inhibition activity of several novel indole melatonin analogues are reported. Compounds have shown variable antioxidant features depending on the substitution pattern. Melatonin and the antioxidant reference compound butyl hydroxy toluen (BHT) were used to compare the antioxidant capability of the compounds synthesized.

Synthesis and antioxidative properties of novel thiazolidinedione/imidazolidinedione compounds as retinoids.

The general term "retinoids" refers to both naturally occurring as well as synthetic compounds which exhibit biological activity similar to vitamin A (retinol). Vitamin A and its two metabolites, retinaldehyde and retinoic acid, are fat-soluble unsaturated isoprenoids necessary for the growth, differentiation and maintenance of epithelial tissues. In this study, we have synthesized thiazolidinedione/imidazolidinedione compounds as retinoids. Their in vitro effects on rat liver microsomal NADPH-dependent lipid peroxidation (LP) levels and superoxide anion formation were determined.

Anti-cancer activity studies of indolalthiohydantoin (PIT) on certain cancer cell lines.

5-(2-Phenyl-3'-indolal)-2-thiohydantoin (PIT) has been evaluated as an anti-cancer compound on several cancer lines organised in to subpanels representing leukemia, melanoma, and cancer of lung, colon, kidney, ovary, breast, prostate and central nervous system by the National Cancer Institute (NCI) anti-cancer drug screen programme. The compound showed inhibitory activity on several cancer cell lines. No information is available on anti-cancer potency of this compound with normal cell lines.

Synthesis and antimicrobial activity of some new flavonyl oxime ether derivatives.

The synthesis of a series of 6 compounds related to 2-(4'-formyl-phenyl)-4]H-1-benzopyran-4-one O-substituted oxime and the results of a study of their biological activity are reported. The structural assignments of the compounds is based upon various spectral data. The prepared compounds were screened for their in vitro antibacterial and antifungal activities. Compound F3 exhibited the best antifungal activity compared with ketoconazole and fluconazole.

Evaluation of anti-HIV activity of 5-(2-phenyl-3'-indolal)-2-thiohydantoin.

The anti-HIV activity of the previously synthesized 5-(2-phenyl-3'-indolal)-2-thiohydantoin I was evaluated. The compound, containing two structural moieties found in highly active anti-HIV agents, exhibited poor activity and rather high cytotoxicity.

The inhibitory effect of benzodiazepine derivatives on the bovine lens aldose reductase enzyme.

The aldose reductase enzyme, involved in the sorbitol pathway which is an important mechanism in regulation of mammalian glucose metabolism, has been known to play a significant role in the initiation of diabetic complications. Numerous chemical substances have been prepared in order to improve the pharmacological profile of inhibition of aldose reductase enzyme. In this study, aldose reductase inhibitory activities of several benzodiazepine derivatives were investigated. The enzyme was obtained from bovine lenses via the ammonium sulphate-protein cut method with several steps. It was found that tetrazepam had a significant inhibitor potency among the other benzodiazepine derivatives showing very slight inhibitor activities that are indicated in terms of percent inhibitor potency at 10(-4) M concentration.

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.

Effects of a benzimidazole compound on monooxygenase activities.

A retinoid-type benzimidazole compound (benzimidazole-tetranaphthalene, BITN) was synthesized and its effects on hepatic cytochrome P450 (CYP) dependent ethoxyresorufin O-deethylase (EROD) and pentoxyresorufin O-depentylase (PROD) enzyme activities were determined in rats in vitro. In vitro addition of BITN in 10(-3) M concentration to the reaction medium caused inhibitions in EROD (94%) and PROD (82%) activities. With the same concentration (10(-3) M) all-trans-retinoic acid (RA) was able to inhibit EROD activity 65% and PROD activity 59% whereas buthylated hydroxytoluen (BHT) inhibited EROD and PROD activities 73% and 62%, respectively. The specific inhibitors of EROD activity (caffeine) and PROD activity (SKF 525A) at 10(-3) M concentration inhibited the corresponding enzymes 33% and 77%, respectively. Thus, these results reveal that the BITN has a stronger inhibitory effect than RA, BHT, caffeine and SKF 525 A on the enzyme activities. Since these enzymes (EROD, CYP 1A1/2 and PROD, CYP2B1) activate polycyclic hydrocarbons, aromatic amines and aliphatic halogenated hydrocarbons to their ultimate mutagenic or carcinogenic forms, and are effective in producing reactive oxygen species such as superoxide, hydroxyl radical and hydrogen peroxide, the new compound, BITN, appears to have a greater anticarcinogenic and antioxidant potential than RA and BHT.

Studies on the synthesis and structure-activity relationships of 5-(3'-indolal)-2-thiohydantoin derivatives as aldose reductase enzyme inhibitors.

A new series of 5-(3'-indolal)-2-thiohydantoin derivatives was synthesized and tested for the ability to inhibit bovine lens aldose reductase (AR) enzyme. The compounds were prepared by condensation of substituted indole-3-aldehyde derivatives with 2-thiohydantoin. The capacity of inhibiting the semi-purified bovine lens enzyme in vitro was observed for several of the compounds tested. One of them was found to be effective in reducing the enzyme activity compared with a corresponding well-known AR inhibitor.

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.

An artificial intelligence approach to the study of the structural moieties relevant to drug-receptor interactions in aldose reductase inhibitors.

The computer-automated structure evaluation program has been used to study 482 compounds relevant to the inhibition of the aldose reductase enzyme. Major activating/inactivating fragments were generated automatically. The significance of these molecular descriptors with respect to the activity of the compounds is discussed.