Mini Reviews in Medicinal Chemistry - Volume 6, Issue 3, 2006

Chemicals and metal ions often induce allergic contact dermatitis. We review here recent advances in the development of in vitro assays for prediction of skin sensitizing potency based on chemical and biological reactivity as well as in the identification of physiological binding partners and immunological pathomechanisms of chemical and metal ion induced disease.

Endocannabinoids are amides, esters and ethers of long chain polyunsaturated fatty acids, which act as new lipidic mediators. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2- AG) are the main endogenous agonists of cannabinoid receptors, able to mimic several pharmacological effects of (-)-Δ9-tetrahydrocannabinol (THC), the active principle of Cannabis sativa preparations like hashish and marijuana. The activity of AEA and 2-AG at their receptors is limited by cellular uptake through an anandamide membrane transporter (AMT), followed by intracellular degradation. A fatty acid amide hydrolase (FAAH) is the main AEA hydrolase, whereas a monoacylglycerol lipase (MAGL) is critical in degrading 2-AG. Here, we will review growing evidence that demonstrates that these hydrolases are pivotal regulators of the endogenous levels of AEA and 2-AG in vivo, overall suggesting that specific inhibitors of AMT, FAAH or MAGL may serve as attractive therapeutic targets for the treatment of human disorders. Recently, the N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD), which synthesizes AEA from N-arachidonoylphosphatidylethanolamine (NArPE), and the diacylglycerol lipase (DAGL), which generates 2-AG from diacylglycerol (DAG) substrates, have been characterized. The role of these synthetic routes in maintaining the endocannabinoid tone in vivo will be discussed. Finally, the effects of inhibitors of endocannabinoid degradation in animal models of human disease will be reviewed, with an emphasis on their ongoing applications in anxiety, cancer and neurodegenerative disorders.

Nerve agents (sarin, soman, cyclosarin, tabun and VX agent) and pesticides (paraoxon, chlorpyrifos, TEPP) represent extremely toxic group of organophosphorus compounds (OPCs). These compounds inhibit enzyme acetylcholinesterase (AChE, EC 3.1.1.7) via its phosphorylation or phosphonylation at the serine hydroxy group in its active site. Afterwards, AChE is not able to serve its physiological function and intoxicated organism is died due to overstimulation of cholinergic nervous system. The current standard treatment of poisoning with highly toxic OPCs usually consists of the combined administration of anticholinergic drugs (preferably atropine) and AChE reactivators (called "oximes"). Anticholinergic drugs block effects of accumulated neurotransmitter acetylcholine at nicotinic and muscarinic receptor sites, while oximes reactivate AChE inhibited by OPCs. Unfortunately, none from the currently used oximes is sufficiently effective against all known nerve agents and pesticides. Therefore, to find new oximes able to sufficiently reactivate inhibited AChE (regardless of the type of OPCs) is still very important task for medicinal chemistry with the aim to improve the efficacy of antidotal treatment of the acute poisonings mentioned. In this paper, the relationship between chemical structure of AChE reactivators and their ability to reactivate AChE inhibited by several nerve agents and pesticides is summarized. It is shown that there are several structural fragments possibly involving in the structure of proposed AChE reactivators. Finally, an attempt of a future course of new AChE reactivators development is discussed.

In this review we present recent studies on the effects of the protein phosphatase inhibitor microcystin on mammalian cells. Whereas high concentrations of microcystin promote liver cell death induced by ROS signalling without the involvement of typical apoptotic proteins, intermediate doses activate classic apoptotic pathways. Low concentrations however, increase liver cell survival and proliferation, and can cause primary liver cancer.

Toll-like receptor (TLR) 9 recognizes synthetic oligodeoxynucleotides (ODN) containing unmethylated deoxycytidyl-deoxyguanosine (CpG) motifs and mimics the immunostimulatory activity of bacterial DNA. Both innate and adaptive immune systems are activated through TLR9 signaling and thus its synthetic agonists or inhibitors have potential significance as a target for therapeutic use in immunological disorders. Interestingly, TLR9 found in the dendritic cells and B cells produce differential outcome in response to structurally distinct CpG-ODNs. While one class of CpG-ODN activates B cells and produce immunoglobulin, other can either redirect plasmacytoid dendritic (pDC) cells to secrete high level of IFNα or myeloid dendritic cells (mDC) to produce Th1-like cytokines and chemokines necessary for asthma control. This review focuses on potential use of various synthetic CpG to modify TLR9 signaling for therapeutic treatment of multiple diseases including cancer, asthma, allergy and systemic lupus erythematosus (SLE).

This review covers our recent advances in the synthesis of unusual amino acids in optically pure form, and their introduction into naturally occurring peptides with specific biological properties, or into modified bioactive peptides, aiming to obtain analogues displaying enhanced performances in term of activity, bioavailability and resistance to enzymatic hydrolysis.

Various environmental, physical and chemical stresses on cells may induce either an overproduction of ROS (Reactive Oxygen Species) or a deficiency of antioxidant enzymes. ROS are responsible for various cellular anomalies like protein damage, deactivation of enzymes, alteration of DNA and lipid peroxidation which in turn leads to pathological conditions like carcinogenesis, reperfusion injury, rheumatoid arthritis, diabetes etc. The regular intake of antioxidants seems to limit or prevent the dangerous effects caused by ROS. Thus, to maintain cellular health, it is important to have a specific and effective antioxidant that scavenges multiple types of free radicals so that it can be used in multiple diseases. Different in vitro and in vivo test systems are available in the literature to assess the free radical scavenging activity of various compounds. Based on the efficiency of free radical scavenging, the compounds are classified into strong, moderate and weak antioxidants. The following review explains the brief procedure and the principle behind various methods available in the literature, which can be used to determine the scavenging of different types of free radicals.

Diabetes is associated with a marked increase in the risk of atherosclerotic vascular disorders, including coronary, cerebrovascular, and peripheral artery disease. Cardiovascular disease (CVD) could account for disabilities and high mortality rates in patients with diabetes. In this paper, we review the molecular mechanisms for accelerated atherosclerosis in diabetes, especially focusing on postprandial hyperglycemia, advanced glycation end products (AGEs) and the renin-angiotensin system. We also discuss here the potential therapeutic strategy that specifically targets CVD in patients with diabetes.

Antisense technology has advanced substantially in the past few decades and now is a wellestablished therapeutic approach in medicinal chemistry, and it may prove to be a valuable tool in the treatment of a wide range of diseases. Phosphorothioate oligonucleotides are among the most important and promising antisense agents. However, the key drawback lies in their polydiastereomerism, which manifests itself in the different chemical and biological properties of the diastereomeric species. Methodologies towards the stereocontrolled synthesis of antisense phosphorothioate oligonucleotides have been well investigated in recent years. In this review, the progress in this field is summarized.

Genistein is a well known protein tyrosine kinase inhibitor. It is structurally similar to 17β- estradiol and exerts antiestrogenic effects. It also affects the signal transduction components Akt, FAK, ErbB-2 and Bcl-2. Key enzymes implicated in cancer invasion are also affected by genistein. A critical evaluation of the effects of genistein on breast cancer growth, signaling and gene expression is presented in this review.

In asthma, inflammatory and structural cells contribute to increased bronchoconstriction acutely and more chronically to airway remodelling. Current asthma therapy doesn't inhibit these features satisfactorily. This review discusses Rho-kinase as a potential drug target, since increasing evidence suggests a central role for this pathway in acute and chronic airway hyperresponsiveness.

In order to evaluate the anti-hyperglycemic effect of natural compounds via the inhibition of α- glucosidase (AGH), the potential inhibitory effect of anthocyanins, caffeic acid analogs, and caffeoylquinic acid analogs have been reviewed. A new AGH assay system to mimic the membrane-bound AGH at the small intestine was proposed and evaluated.

Cardiac hypertrophy is a response of the heart to a wide range of extrinsic stimuli, such as arterial hypertension, valvular heart disease, myocardial infarction, and cardiomyopathy. Although this process is initially compensatory for an increase workload, its prolongation frequently results in congestive heart failure, arrhythmia, and sudden death. Cardiac hypertrophy is associated with an increase in glucose utilization and a decrease in fatty acid oxidation. It is unclear at present, however, which consequences might result from impaired oxidation of fatty acids in the heart, but several studies have demonstrated that substrate utilization is important in the pathogenesis of cardiac hypertrophy. Here we will focus on the effects of cardiac hypertrophy on the activity of Peroxisome proliferator-activated receptors (PPARs), ligand-activated transcription factors that regulate the expression of genes involved in fatty acid uptake and oxidation, lipid metabolism and inflammation. Interestingly, activation of the Nuclear Factor (NF)-κB signaling pathway, which is one of the most important signal transduction pathways involved in the hypertrophic growth of the myocardium, may suppress the activity of the PPARs, affording a link between cardiac hypertrophy and the fall in fatty acid oxidation in the hypertrophied heart. As a result, inhibition of NF-κB activation during cardiac hypertrophy may also ameliorate cardiac fatty acid oxidation, achieving a better improvement in the prevention or inhibition of this pathological process.