Evaluation of ED[50] and 5alpha-reductase inhibitor activities of some thiopyrimidine, pyrane, pyrazoline and thiazolopyrimidine derivatives

In this work, twenty-one thiopyrimidine [1-21] candidates containing a pyrane, pyrazoline and thiazolopyrimidine ring screened for their ED[50] and 5alpha-reductase inhibitors comparable to that of Anastrozole as positive drug. Some of the tested product showed moderate 5alpha-reductase inhibitors with lower toxicity. The detailed ED[50] and 5alpha-reductase inhibitor activities of the synthesized compounds were studied

Glucagon-like peptide-1 derivatves and dipeptidyl peptidase-IV inhibitors. New hope for the treatment of type-2 dibetes

Glucagon-like peptide GLP-1 is an endogenous insulinotropic/glucagonostatic hormone that acts in a self-limiting mechanism. It is a multifunctional hormone that leads to insulin release stimulation, liver glucagon breakdown suppression, upregulation of islet cell proliferation, and neogenesis and retardation of gastric emptying. The short half-life and high renal clearance due to degradation via dipeptidyl peptidase-IV DPP-IV, and active glomerular filtration rate make this hormone ineffectual as an exogenous agent. More stable and long acting GLP-1 analogues and DPP-1 inhibitors have been developed with promising clinical value for the treatment of type-2 diabetes. The GLP-1 derivatives have the advantage of decreasing body weight while the DPP-IV inhibitors can be administered orally up to once daily. The mechanism of action as well as the tolerable side effect is astounding. This review article covers this new generation of anti-diabetics

Role of molybdenum hydroxylases in diseases

The role of molybdenum-containing enzymes, aldehyde oxidase and xanthine oxidase in the production of reactive oxygen species has been discussed in term of mechanism of action. Unlike cytochrome P450 and other monooxygenase systems, the molybdenum hydroxylases carry out their reactions using water rather than molecular oxygen as the source of the oxygen atom incorporated into the product, and generated rather than consumed electrons. Aldehyde oxidase and xanthine oxidase differ in their substrates and inhibitor specificity. While aldehyde oxidase is a predominant oxidase, xanthine oxidase can undergo inter-conversion between oxidase/ dehydrogenase forms under pathological conditions such as ischaemia. Nevertheless, the wide range of drugs, xenobiotics and endogenous chemicals that interact with these enzymes, particularly aldehyde oxidase, highlight the importance of these enzymes in drug oxidation, detoxification and activation. Aldehyde oxidase and xanthine oxidase have been linked to some diseases such as neurodegenerative and ischaemic disorders, respectively. In vivo, oxidation of aldehyde oxidase-substrates such as ethanol-derived acetaldehyde, retinal and NADH may alter the balance of ROS production by this enzyme leading to neurological disorders, such as amyotrophic lateral sclerosis, Parkinson's disease and schizophrenia. In addition, aldehyde oxidase has been implicated in pathophysiology of alcohol liver injury, visual processes, synthesis of retinoic acid and reperfusion tissue injury. Under pathological conditions, such as ischaemia-reperfusion injury, both enzymes may participate

In Vitro Inhibitory effect of quinolinic acid on aldehyde oxidase activity of guinea pig liver: a proposed mechanism

The aim of the present study was to investigate the interaction of quinolinic acid [QA] with partially purified guinea pig liver aldehyde oxidase in terms of superoxide anion production [02'], hydrogen peroxide [H202] formation and the overall substrate oxidation. Due to the structural similarity of QA to some aldehyde oxidase substrates, such as 2-pyrimidinone, the effect of QA on aldehyde oxidase activity has been investigated in the present study. The interaction between QA and aldehyde oxidase has been measured by spectophotometerically and fluorimetrically methods using phthalazine [a classical heterocyclic substrate] and indole-3-aldehyde [an excellent aldehyde substrate]. The inhibitory effects of QA on indole-3-aldehyde and phthalazine oxidation, superoxide anion production and hydrogen peroxide formation were found to be competitive inhibition in all three cases [Ki = 77-106 AM, r > 0.995, p<0.005]. QA inhibitory effect on aldehyde oxidase suggests that it may play a role in inhibition of initial rates of superoxide anion formation but may increase overall production of this radical by aldehyde oxidase. QA had a dual effect on superoxide anion production from the two substrates; initial rates were reduced but after 5-8 minutes reaction rates were enhanced. Both effects were concentration dependent