Current Medicinal Chemistry - Volume 12, Issue 4, 2005

Helicobacter pylori infection has been indicated as the main pathogenic factor in the development of chronic gastritis, peptic ulcer disease, and gastric malignancies. Although the vast majority of infected subjects do not carry but a mild, asymptomatic gastritis, still there are some cases in which the eradication of the infection appears mandatory. This review addresses current anti-Helicobacter regimens and pharmacological resources, and highlights the pros and cons of each of them, according to the most recent and reliable clinical trials. Also, basic recommendations are given, regarding treatment choice in the event of the failure of a first or second line eradicating strategy, and about the implementation of standard regimens with newer antibacterial devices as probiotics.

Over the past decade, 11 human genes belonging to the solute linked carrier (SLC) 26 family of transporters, have been identified. The SLC26 proteins, which include SAT-1, DTDST, DRA / CLD, pendrin, prestin, PAT-1 / CFEX and Tat-1, are structurally related and have been shown to transport one or more of the following substrates: sulfate, chloride, bicarbonate, iodide, oxalate, formate, hydroxyl or fructose. Special interest has focused on four members of the SLC26 family that are associated with distinct recessive diseases: (i) Mutations in SLC26A2 lead to four different chondrodysplasias (diastrophic dysplasia, atelosteogenesis type II, achondrogenesis type IB and multiple epiphyseal dysplasia); (ii) SLC26A3 is associated with congenital chloride diarrhea; (iii) SLC26A4 is associated with Pendred syndrome and non-syndromic deafness, DFNB4; and (iv) SLC26A5 is defective in non-syndromic hearing impairment. This review article summarizes current information on the pathophysiological consequences of mutations in the human SLC26A2 to A5 genes.

Recent developments in the field of haemostasis and thrombosis highlighted the crucial role of the tissue factor / factor VIIa complex (TF / FVIIa) in the initiation of coagulation processes. Nowadays, anticoagulant therapies involving heparin or coumarin derivatives, thrombin or factor Xa inhibitors are generally associated with side effects such as bleeding and thrombocytopenia. In this context, the inhibition of TF, FVIIa and their complex by efficient antithrombotic drugs represents a new strategy to reduce this bleeding and to prevent thrombosis events. Moreover, TF / FVIIa inhibition is shown to be useful in the treatment of biological processes independent of the clotting cascade such as angiogenesis and cancer. Among the natural and genetically engineered TF / FVIIa inhibitors, injections of the recombinant protein rNAPc2 show clinical improvements, such as reduced bleeding and thromboembolism, over classical drugs used in the therapy of coronary angioplasty and hip or knee replacement surgery. The knowledge of the 3D-structure of TF / FVIIa complex and examination of co-crystal data of some drugs bound to this complex led to the design and synthesis of numerous TF / FVIIa inhibitors. Among them, the p-amidinophenylurea 18 (Ki = 0.027 μM), the pyrimidinones PHA-927 (30, IC50 = 0.016 μM) and PHA-798 (31, IC50 = 0.014 μM) and the pyridinone 37 (IC50 = 0.052 μM) are highly potent inhibitors of the TF / FVIIa complex, deprived of activity towards thrombin (IC50 > 30-100 μM) and factor Xa (IC50 > 10-100 μM), other proteases involved in the coagulation cascade. Both pyrimidinones prevent arterial thrombosis in non-human primate models of thrombosis and represent a safe approach to anti-thrombotic therapy in patients with cardiovascular risk factors.

The aminocoumarin antibiotics novobiocin, clorobiocin and coumermycin A1 are produced by different Streptomyces strains and are potent inhibitors of DNA gyrase. The biosynthetic gene clusters of all three antibiotics have been cloned and sequenced, and the function of most genes contained therein has been elucidated. In the last years, a number of “unnatural” aminocoumarins could be generated using the genetic information for the biosynthesis of these antibiotics. The investigated enzymes of aminocoumarin biosynthesis have less-than-perfect substrate specificity, facilitating the production of new antibiotics by various methods. Several new aminocoumarins could be produced by targeted genetic manipulation in the natural producers, but also in heterologous host Streptomyces coelicolor after expression of the respective gene cluster. Mutasynthesis experiments, i. e. generation of a cloQ-defective mutant of the clorobiocin producer and feeding of 13 different structural analogs of 3-dimethylallyl-4-hydroxybenzoic acid to this mutant, allowed the isolation of 32 new aminocoumarins. These compounds contained, instead of the genuine 3-dimethylallyl-4- hydroxybenzoyl moiety, the externally added analogs as the acyl components in their structures. Production of new aminocoumarins was also achieved by chemoenzymatic synthesis in vitro. Several biosynthetic enzymes have been heterologously expressed, purified und used for chemoenzymatic synthesis. The structures of the new aminocoumarins were elucidated by NMR and mass spectroscopy. Their inhibitory activity on gyrase in vitro as well as their antibacterial activity was determined. These results give further insight into the structure-activity relationships of aminocoumarins.

It has long been considered that mitochondrial DNA disease is a rare genetic disorder causing neuromyopathy. However, alterations of mitochondrial DNA recently have been recognized to play an important role in the pathogenesis of so-called common diseases such as heart failure, diabetes, and cancer. Although some of these alterations are inherited, more and more attention is being focused on the accumulation of mitochondrial DNA mutations in somatic cells, particularly terminally differentiated cells such as cardiomyocytes and neurons that occurs with age. Mitochondrial DNA is more vulnerable to alteration than nuclear DNA, mainly for two reasons. First, mitochondria are a major source of intracellular reactive oxygen species (ROS). Therefore mitochondrial DNA is under much stronger oxidative stress than is nuclear DNA. Second, mitochondria have a matrix-side negative membrane potential for oxidative phosphorylation. This membrane potential concentrates lipophilic cations inside mitochondria up to ~1,000-fold. Unfortunately, some therapeutic reagents are lipophilic cations, and such exogenously added chemicals are prone to damage mitochondria. AZT, an anti-HIV drug, causes mitochondrial myopathy as a side effect, which is a typical example of how chemotherapeutics adversely affect metabolism of mitochondrial DNA. In this review, we focus on ROS and chemical damage of mitochondrial DNA in common diseases.

Peripheral arterial disease (PAD) is a common condition associated with an increased risk of coronary heart disease, myocardial infarction and stroke. It follows that PAD merits aggressive preventive treatment that includes lipid lowering drugs (mainly statins). This review summarises the current knowledge concerning the use and mechanisms of action of statins in patients with PAD. Statins not only lower the risk of vascular events, but they also improve the symptoms associated with PAD. There is also evidence that statins reduce surgical mortality and improve graft patency and limb salvage. Because of the high risk, a more aggressive goal [i.e. low density lipoprotein cholesterol (LDL-C) of 70 mg / dl; 1.8 mmol / l] [National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III), revised guidelines 2004] should be considered to maximally reduce the atheroma burden and related events. Not all statins can achieve this LDL-C target. Furthermore, there may be a need to use an additional lipid lowering drug so as to achieve the LDL-C goal and benefit from the different modes of action. Statins exert beneficial pleiotropic effects on haemostasis, the vasculature and inflammatory markers. There is also evidence that statins improve renal function (the plasma creatinine level is considered as an emerging vascular risk factor). Since PAD patients often take several drugs, there is a need to carefully consider their selection so as to maximize benefits and minimize adverse effects. Patients with PAD often do not receive adequate lipid lowering treatment. This situation needs to change.

During the past five years, several members of the KCNQ potassium channel gene family have been identified with a high degree of CNS specificity. Within the KCNQ family, the combination of the KCNQ2 / KCNQ3 proteins, and the KCNQ5 / KCNQ3 arrangement has been identified as the molecular correlates of the different M-currents. Several lines of evidence are emerging demonstrating the importance of these channels in regulating neuronal excitability; for example, determination of the excitability threshold, firing properties, and responsiveness of neurons to synaptic inputs. Recent studies have shown that KCNQ openers have potential for the treatment of several CNS disorders characterized by neuronal hyperexcitability, such as migraine, epilepsy and neuropathic pain. This article reviews the recent developments of KCNQ potassium channel openers.

Conventional insecticides are highly toxic to many living organisms as well as to the environment; consequently, new biorational and more specific approaches to pest control have been developed. In this paper, we present an update of those approaches resulting from studies on inhibition of enzymes involved in key processes of insects life, particularly growth, molting and development of larvae and intraspecific communication of adults. The enzymes covered include pheromone degrading enzymes, pheromone biosynthetic enzymes, oxidoreductases, juvenile hormones, juvenile hormone epoxide hydrolases, proteases, molting hormones and phenoloxidases. Although these approaches refer to control of insect pests, many of them can be in principle also considered suitable for medicinal chemistry studies, since the mechanism of action of these inhibitors on related enzymes is quite similar, if not equal, in both fields.

The discovery of endogenous opioid peptides with their limited receptor selectivity more than two decades ago implicated their involvement in analgesia and initiated efforts to understand the molecular mechanisms underlying their action. Opioid peptides mediate their physiological and pharmacological effects through three major opioid receptor types (μ, δ, κ), but the role of each of these receptors is not easy to distinguish. There has therefore, been an increasing need for potent and selective agonists and antagonists in this area. The incorporation of conformational constraints into analogs of biologically active peptides is a well-known approach for enhancing receptor selectivity and modulating efficacy. Conformational restriction has proven a valuable means for assessing disparities between the peptide binding characteristics at each of the opioid receptor types, since peptide analogs designed with appropriate conformational constraints possess the ability to adopt the conformation required for interaction at one receptor type but not another. In efforts to obtain better conformational integrity various conformationally restricted analogs of endogenous opioid peptides have been developed. In this paper we review the development of opioid analogs whose conformation was restricted either globally through different types of cyclization (such as amide bond formation, disulfide and monosulfide bridges, carbonyl and amine bridges) or locally, through incorporation of side-chain conformational constraints at a specific amino acid residue by synthesizing cyclic amino acids or constraining torsion angles by suitable substitutions. These two approaches have led to the development of potent and very selective agonists and antagonists at all three opioid receptor types.

Chalcone is a unique template that is associated with several biological activities. In this review, an update of the cytotoxic and chemoprotective activities of chalcones is provided. Cytotoxicity against tumour cell lines may be the result of disruption of the cell cycle, inhibition of angiogenesis, interference with p53- MDM2 interaction, mitochondrial uncoupling or induction of apoptosis. Structural requirements for cytotoxic activity vary according to the mechanisms of action. For anti-mitotic activity, the presence of methoxy substituents, a-methylation of the enone moiety and the presence of 2' oxygenated substituents are favourable features. Conformational restraint of the chalcone template generally leads to a decrease in cytotoxic activity. Chemoprotection by chalcones may be a consequence of their antioxidant properties, mediated via inhibition or induction of metabolic enzymes, by an anti-invasive effect or a reduction in nitric oxide production. Hydroxyl and prenyl substituents are associated with antioxidant properties and induction of quinone reductase activities. The thiol reactivity of chalcones is likely to contribute to both cytotoxic and chemoprotective properties of these compounds.