Current Medicinal Chemistry - Volume 15, Issue 14, 2008

DNA methyltransferases (DNMTs) are important regulators of gene transcription and their roles in carcinogenesis have been a topic of considerable interest in the last few years. Diverse classes of chemical compounds including nucleotide analogues, adenosine analogues, aminobenzoic derivatives, polyphenols, hydrazines, phthalides, disulfides and antisenses are being discovered and evaluated as DNMT inhibitors targeting DNA hypermethylation. Among them, 5-Azacytidine 5 and Decitabine 6 were launched recently. Several other compounds are under clinical trials. Some of these compounds were discovered from structure-based drug design. These compounds exert their DNA methylation inhibitory by different mechanisms. This review will present a brief account of various DNA methyltransferases and their biological functions, with focus on actuality of design and synthesis of various inhibitors of DNA hypermethylation as anticancer drugs.

The methylhydrazine derivative Procarbazine (PCZ) as monotherapy or in combination with CCNU and vincristine (PCV) was evaluated in a vast number of clinical trials and is still used in patients with high-grade and low-grade gliomas. The compound is an antineoplastic agent with multiple sites of action. It inhibits incorporation of small DNA precursors, as well as RNA and protein synthesis. PCZ can also directly damage DNA through an alkylation reaction. The drug is not cross-resistant with other mustard-type alkylating agents. As PCZ was in almost all trials used in a combination with CCNU and Vincristin, the efficacy can only be evaluated in the view of the PCV regimen. The published data suggest a role of PCV as a salvage regimen, especially in oligodendroglial tumors; however, well designed studies with high evidence are rare in all entities. This article summarizes the existing data with the goal to define the role of PCZ/PCV in modern neurooncology.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation and remodeling of extracellular matrix proteins that are associated with the tumorigenic process. MMPs promote tumor invasion and metastasis, regulating host defense mechanisms and normal cell function.Thus, MMP inhibitors (MMPIs) are expected to be useful for the treatment of diseases such as cancer, osteoarthritis, and rheumatoid arthritis. A vast number of MMPIs have been developed in recent years.With the failure of these inhibitors in clinical trials,more efforts have been directed to the design of specific inhibitors with different Zn-binding groups. This review summarizes the current status of MMPIs, the design of small molecular weight MMPIs , a brief description of available threedimensional MMP structures, a review of the proposed therapeutic utility of MMPIs, and a clinical update of compounds that have entered clinical trials in humans.

Nitric oxide (NO) produced by endothelial NO synthase (NOS) in low concentrations is a unique messenger molecule with key homeostatic functions concerning the prevention of pathological vascular and tissue changes such as increases in blood pressure, platelet degranulation, mononuclear cell infiltration, cell proliferation and extracellular matrix protein accumulation. This is in contrast to high levels of NO derived from inducible NOS which act as detrimental effector molecules and free radicals in immune response. Deficiency in NO's protective signaling actions is a major characteristic in numerous experimental and human disease situations. The main function of the NO signaling pathway is activation of the soluble guanylate cyclase (sGC) enzyme with subsequent generation of cyclic guanosine monophosphate (cGMP) as a second messenger and downstream mediator. In the past, attempts to overcome deficiency in endothelial NO effects were focused primarily on increasing the supply with the NO precursor L-arginine or on the use of directly NOreleasing compounds. The clinical impact of these strategies, however, was rather limited. Recent state-of-the-art studies have revealed that NO signaling is highly regulated at the transcriptional level and that deficiency in NO signaling correlates closely with pathological changes. In parallel efforts, novel pharmacological compounds which specifically enhance NO/cGMP signaling have been developed and have demonstrated remarkable efficacy in experimental disease settings. In this review, we summarize the current state of knowledge on the impairment of NO/cGMP signaling and about its pharmacological stimulation. In the first part, experimental renal fibrosis, i.e. the tandem rat model of acute anti-thy1 glomerulonephritis and progressive anti-thy1 renal fibrosis will serve as a paradigm for introducing this new and exciting field. In the second part, we will address the most recent findings on NO signaling in non-renal diseases. Together, these results point out that deficiency in NO/cGMP is a common key pathway as well as a novel therapeutic target in a number of diseases.

Currently, growth factors which have been identified in hematopoiesis and angiogenesis are re-considered as therapeutical agents in a number of neurological diseases, mainly neurodegenerative disorders like Parkinson's Disease, amyotrophic lateral sclerosis (ALS), or cerebrovascular events such as stroke. Among these growth factors, erythropoietin (EPO) and granulocyte colony-stimulating growth factor (G-CSF) are the most prominent. With regard to neurological disease, EPO has been tested in clinical trials for potential use in stroke, schizophrenia, and addiction, G-CSF is currently under clinical investigation for stroke treatment. The major advantage of these growth factors is their well-described pharmacological behavior and their clinical use over several years. A number of mechanisms of action in the CNS have been identified that are probably important for the beneficial action of these factors in animal models of disease, the most relevant relating to neuroprotection, neuroplasticity and stem cell growth and differentiation. In this review, we will discuss the current efforts and prerequisites of novel growth factor therapies for neurodegenerative diseases with regard to their possible mechanism of action on the molecular level and their effects on brain-derived stem cell populations. Additionally, we will describe the necessities for future research before such therapies can be envisioned.

Bacterial urinary tract infections (UTI) are frequently found in the outpatient as well as in the nosocomial setting. The bacterial UTI can be stratified into uncomplicated and complicated UTI. Antibiotic resistance is continuously increasing in uncomplicated as well as complicated UTI. In uncomplicated UTI efforts are made to use antibiotic substances exclusively for this indication. In complicated UTI as broad spectrum antibiotics are increasingly used, the higher the antimicrobial resistance rates are reported. There are two predominant aims in the antimicrobial treatment of both uncomplicated and complicated UTI: 1.) rapid and effective response to therapy, prevention of complications and prevention of recurrence in the individual patient treated, and 2.) prevention of emergence of resistance to anti-infective agents in the microbial environment. The use of antibiotics has to keep up with the continuous change in antimicrobial resistance and the tailored needs in the individual patient. Antibiotic substances therefore need to become evaluated for each indication and continuously followed for clinical usage. The knowledge of structure-activity relationships of antimicrobial substances and bacterial resistance mechanisms to antibiotics help to use antibiotics better in daily routine and design new derivatives and substances. The aim of this review is to describe the chemistry and structure-activity relationships of current antibiotics and promising substances in development for the treatment of UTI.

Cannabinoids in current use such as nabilone activate both CB1 and CB2 receptors. Selective CB2 activation may provide some of the therapeutic effects of cannabinoids, such as their immuno-modulatory properties, without the psychoactive effects of CB1 activation. Therefore, cannabinoid CB2 receptors represent an attractive target for drug development. However, selective and potent CB2 agonists remain in development. CB1 and CB2 differ considerably in their amino acid sequence and tertiary structures. Therefore, clinical development of potent and selective CB2 agonists is probable. Mutational and ligand binding studies, functional mapping, and computer modelling have revealed key residues and domains in cannabinoid receptors that are involved in agonist and antagonist binding to CB1 and CB2. In addition, CB2 has undergone more rapid evolution, and results for ligand binding and efficacy cannot be automatically extrapolated from rat or mouse CB2 to human. Furthermore, loss of CB1 affinity is a crucial property for CB2-selective ligands, and although rat CB1 is 97% homologous with human CB1, critical differences do exist, with potential for further exploitation in drug design. In this paper we briefly review previous cannabinoid receptor models and mutation/binding studies. We also review binding affinity ratios with respect to CB1 and CB2. We then employ our own models to illustrate key cannabinoid receptor residues and binding subdomains that are involved in these differences in binding affinities and discuss how these might be exploited in the development of CB2 specific ligands. Published reports for species specific binding affinities for CB2 are scarce, and we argue that this needs to be corrected prior to the progression of CB2 agonists from pre-clinical to clinical research.

Over the last 50 years, increasing evidence has documented the ability of cardiac non-neuronal cells to synthesize and release catecholamines (CAs) and the vasorelaxant natriuretic peptides (NPs), which both regulate cardiovascular homeostasis in health and disease. This knowledge has firmly established the concept of the heart as an endocrine organ. The contents of this frame have been richly expanded by the identification of an increasing number of intracardiac endocrine modulators, including Chromogranin-A (CgA) and its derived peptides. In the rat heart, CgA is co-stored and co-released with Atrial NP (ANP) in non-adrenergic myoendocrine atrial cells as well as in atrial and ventricular Purkinje fibres. In the ventricular myocardium of the human hypertrophic and dilated heart, CgA colocalizes with B-type NP (BNP). CgA is the precursor of biologically active peptides produced by proteolytic cleavage. One of them, the human recombinant 1-76 CgA-derived vasostatin-1 (VS-1), is an inhibitor of cardiac contraction and relaxation, a non-competitive counter-regulator of β-adrenergic stimulation and a protecting agent in ischemic preconditioning. Therefore, it may function as a cardiocirculatory homeostatic stabilizer, particularly in the presence of intense adrenergic stimuli, e. g. under stress responses. Since in patients with chronic heart failure circulating CgA levels increase up to 10-20 nM, depending on the severity of the disease and are independent prognostic indicators of mortality, knowledge on the physio-pathological significance of locally produced and/or circulating CgA-derived peptides, as attemped in this synopsis, may pave the way for clinically-oriented cardiovascular applications.