Mini Reviews in Medicinal Chemistry - Volume 8, Issue 9, 2008

Small molecules targeting p53 represent an emerging group of potentially useful agents for the improvement of antitumor therapy. These modulators include agents that activate wild-type p53 or reactivate mutant p53 and inhibitors of p53 functions. Preclinical evidences support the interest of combination strategies with conventional antitumor agents.

Glutamine synthetase (E.C. 6.3.1.2) - an enzyme catalyzing formation of glutamine from glutamate and ammonium ion, is one of the most important enzymes in nitrogen metabolism. Due to glutamine synthetase activity, inorganic nitrogen is incorporated in the cell metabolism and is further used in biosynthesis of several highly important metabolites. The first part of the review presents the long-dating research on inhibitors of glutamine synthetase which started with the discovery of methionine sulfoximine in 1949. Since that time several inhibitors of this enzyme, classified in the following groups: derivatives of methionine sulfoximine, phosphorus containing analogues of glutamic acid, bisphosphonates and miscellaneous inhibitors, have been developed and described. Analysis of their structure-activity relationships is presented in some detail. The second part of the paper is dedicated to potential medical application of glutamine synthetase inhibitors, which proved to act as effective anti-tuberculosis agents with high selectivity towards the pathogenic bacteria. Moreover, it was also shown that glutamine synthetase inhibitors could be successfully applied in cancer therapy.

Impaired wound healing leads to infection and tissue necrosis. This has spurred the search for wound healing agents derived from natural and non-natural sources. Although natural products are widely used as lead compounds for the design of therapeutic drugs, few studies have looked for potential wound healing compounds in nature. In this review, we briefly discuss each phase of the wound healing process. Examples of natural and non-natural products with wound healing activities are listed, and the structure-activity relationship of fifty one compounds are described. An understanding of how these compounds exert their activities in biological systems is essential for their future development and application as wound healing agents.

Dendrimers as a new kind of polymer have been studied for medical applications mainly in two aspects: drug delivery and gene delivery. The unique characteristics, such as uniformity, monodispersity and the ability to functionalize their terminal groups with various targeting agents distinguish them as versatile carriers. In the paper the recent advances of dendrimer in gene transfer vehicles and drug delivery are separately reviewed. These advances illustrate the direction of the future development of dendrimers.

Protein folding in the cell is a tightly regulated process, involving a series of proteins, from molecular chaperones to proteases that assist the folding process and monitor the quality of the final product. Despite this control, genetic or sporadic factors may compromise protein folding and the folded state resulting in the formation of non-native misfolded, destabilised, aggregated or fibrillar species. These are hallmarks of the so-called protein conformational disorders, in which the altered protein conformations result in cell toxicity, functional deficiency or lead to dominant negative effects. Examples of such pathologies include neurodegenerative and metabolic disorders. In recent years, it has become clear that several different small chemical compounds such as osmolytes, protein inhibitors, ligands and cofactors exert a chemical chaperoning effect and are able to rescue folding and trafficking defects, minimising or partly overcoming the pathological consequences of protein misfolding. Here we review the different types of chemical chaperones and provide a structural and energetic rationale for their action. Examples of chemical chaperoning are overviewed and discussed on the basis of the reported effects exerted by chemical compounds at different stages of the protein folding process and protein conformational states.

Apoptosis in atherosclerotic lesions is triggered by inflammatory processes, both via cell-cell contact and by cytokines and oxidized lipids. The role of apoptosis in atherogenesis is dual, depending on the stage of the plaque: In early stages, apoptotic death of smooth muscle - and inflammatory cells, such as lymphocytes and macrophages, may delay atherosclerotic process. However, once the plaque is formed, apoptosis may lead to plaque rupture and thrombosis.

Azathioprine is an immunosuppressive and steroid-sparing purine analogue, used in the treatment of several autoimmune diseases. In multiple sclerosis, available evidence suggests that oral azathioprine reduces relapse rates, provides a slight benefit on disability, and reduces new inflammatory lesions. Here, we focus on molecular mechanisms of Azathioprine and on its usefulness in multiple sclerosis.

Virtual screening is a knowledge driven approach. Therefore, synergies between different virtual screening methods using information about the drug target as well as about known ligands in combination promise the best results. Finding novel active scaffolds is often a more important success criterion than hit rates of virtual screens. Novelty should also be considered in balance with often weaker activities of virtual screening hits. Virtual screening is most effective if performed in iterations following up on weak primary hits of interest through testing of structural analogs and additional synthesis of compounds.

Asthma is a chronic heterogeneous inflammatory disease of the respiratory system in which numerous cytokines play a significant role. Among them TNF-α (tumour necrosis factor α), a proinflammatory cytokine, has a predominant role in orchestrating airway inflammation and affecting treatment outcome. In this review we attempt to summarize the involvement of TNF-α in the pathogenesis of asthma, illustrate variations of TNF-α gene that potentially influence asthma phenotype and highlight promising therapies by blocking the production of TNF-α or inhibiting its action. A cytokine specific target therapy seems to be very promising since agents that block TNF-α slow disease progression, suppress inflammation and in some cases induce remission of chronic inflammation.

This review will discuss the structural determinants and requirements necessary for estrogen receptors alpha and beta selectivity and ligand-receptor binding affinity. In addition, strategies likely to result in the development of a pharmacophore model that account for the differences in estrogenic effects between different ligands will be discussed.

Ischemic preconditioning (PC) and postconditioning (PostC) are endogenous mechanisms of protection of the ischemic heart. In brief, short cycles of sublethal ischemia separated by brief periods of reperfusion render the heart resistant to infarction from a subsequent lethal episode of prolonged ischemia. Although PC is a powerful form of protection, its clinical application is limited because of ethical and practical reasons. It is of interest that multiple very short periods of ischemia and reperfusion applied at the onset of reperfusion are also capable in limiting the infarct size. In fact, the short ischemic insults in PC have to be applied before the onset of sustained period of ischemia which cannot be precisely anticipated. On The contrary, the very brief insults in postconditioning (PostC) have to be applied immediately after the end of the long ischemia thus making the intervention more easily applicable. Both mechanisms reduce the infarct size by limiting the reperfusion injury. Pharmacological PC and PostC represent ideal alternatives that may substitute the short ischemic insults for pharmaceuticals means. The components of PC share two pathways, one that involves the mitochondrial KATP channels- free radicals and PKC and another one that involves adenosine and PKC. Reperfusion injury salvage kinases (RISK) prevent the mitochondrial permeability transition pores (mPTP) which destroy the mitochondria and cause cell death. PC via PKC and PostC via gradual restoration of pH at reperfusion up-regulate RISK and preserve viable part of the ischemic region of the heart. In order to confer pharmacological protection, novel therapeutic strategies, based on the knowledge of the ligands, of the receptors and of the intracellular signaling pathways have emerged. Adenosine, nicorandil and other agents have been already used as pharmacological mimetics of ischemic PC in multicenter trials. Furthermore, agents that increase RISK or directly prevent mPTP are also under investigation as PostC analogues. We summarize recent studies focused on the pharmacological interventions and on the discovery of novel agents that may reduce the infarct size.