Synthesis and investigation of novel shelf-stable, brain - specific chemical delivery system

A 1,4-dihydropyridine - pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs into the brain. Monoamine oxidase inhibitors [MAOIs] were used as a model example to be delivered into the brain. Chemical and biological oxidations of these compounds were investigated. The prepared 1,4-dihydropyridines were subjected to various chemical and biological oxidation to evaluate their ability to cross blood brain barrier [BBB], and to be oxidized biologically into their corresponding quaternary compounds. 1-[Ethoxy-carbonylmethyl]-3,5-bis[N-[2-fluoro-benzylideneamino] carbamoyl]-1,4-dihydropyridine [31] proved to cross BBB in adequate rate and converted by the oxidizing enzymes into the corresponding quaternary salt N-[ethoxycarbonylmethyl]-3,5-bis [N-[2-fluorobenzylideneamino] carbamoyl] pyridinium bromide [20]. Stability studies of the synthesized chemical delivery systems [CDSs] at various pH values and temperatures showed that the shelf life time of a solution containing compound 31 is 20.53 days at 5°C, which recommend a lower storage temperature for such solutions. The prepared CDSs proved to be fairly stable for powder form storage. The stability of the prepared compounds is attributed to the conjugation of the two carboxylic functions at C3 and C5 of the pyridine ring with their adjacent double bonds. These results are in consistency with the original rationale design

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

Drugs as enzyme accelerates

Structurally specific drugs owe their actions through binding to specific receptors or acceptors enzymes are considered as one of those specific targets. Drug action on enzymes and its pharmacological response may be obtained through stimulation, induction, activation, reactivation or inhibition of a specific enzyme. Enzyme acceleration is a broad term, which could accommodate all of the aforementioned categories except inhibition, which is not within the scope of this discussion. This review will cover the effects of synthetic or natural deugs in the potentiation of enzymatic systems involved in certain diseases as a result of their deficiency or inadequate vitalization

Synthesis and antitumor activity of certain thienopyridine and pyridothienopyrimidine derivatives

A series of cyclopenteno[b] or tetrahydrobenzo[b]thiophenes, tetrahydrothieno[2,3-c]pyridines and tetrahydropyrido[4',3' :4,5]thieno[2,3-d]pyrimidines was synthesized as antitumor agents. Most of the tested compounds showed cytotoxic effect [GI[50] < 10 [micro]M] against the growth of P388 leukemia cells. Ethyl2-phenylsulphonamido-4,5,6,7-tetrahydrobenzo[b]thiophen-3-carboxylate [lla], Ethyl 2-[4- bromo-phenylsulphonamido]-4,5,6,7-tetrahydrobenzo[b]thiophen-3-carboxylate [llb], Ethyl 2-[4-methylphenyl-sulphonamido]-4,5,6,7-tetrahydrobenzo[b]thiophen-3-carboxylate [IIc], Ethyl 2-[4-methoxybenzamido]-4,5,6,7 -tetrahydro[b]thiophen-3-carboxylate [IIIc] and N-[4-methylphenyl] N-[3-carbo-ethoxy-6-methyl-4,5,6,7-tetrahydrothieno[2,3-c] pyridin-2-yl] thiourea [lVc] showed strong potency [GI [50]; 0.8, 1.15,2.09, 1.3,2.25 [micro]M; respectively]. The detailed synthesis, spectroscopic and biological data are reported