Mini Reviews in Medicinal Chemistry - Volume 6, Issue 7, 2006

NAD kinase is an essential enzyme, which plays a key role in cellular energy and signal transduction systems. Inthis report, the recent studies on the features of bacterial and human NAD kinases are summarized. They include detailedkinetic and structural analyses and highlight important differences, which could be exploited for the design of novelselective antimicrobial drugs.

1,4-Dihydropyridine (1,4-DHP) derivatives nifedipine of which the prototype, are the most popular drugs having calcium antagonistic activity. Fused 1,4-dihydropyridines (DHPs) have also exhibit calcium modulatory activities. In this article, weemphasizecalcium channels and fused 1,4-DHP derivatives affecting calcium channels. In addition, the basic considerations of synthesis, metabolism, structure-activity relationships and the latest developments on fused 1,4-DHP derivatives will be reviewed. This review also has extended examples of fused 1,4-DHP derivatives having cited activities synthesized by our group.

Tumor-targeted chemo- or gene-therapies is a new form of treatment which provides the benefits ofreducing systemic toxicity, increasing the tolerance, and enhancing therapeutic efficacy. This review willdiscuss the discovery, function, application, and mechanism by which the short peptides (5-9) work for tumor-targeted gene or drug delivery.

Myostatin is a negative regulator of muscle mass. Important advances in our understanding of thecomplex biology of this factor have revealed the therapeutic potential of antagonizing the myostatin pathway. Herewe present the rationale for evaluating anti-myostatin therapies in human muscle-wasting disorders.

The better understanding of the mechanisms of inflammatory bowel disease has driven our progress intothe development of new biological therapies targeting specific molecules. Anti-TNFα biologic compounds have shown great efficacy particularly in Crohn's disease. Infliximab (an IgG1 mouse/human chimeric monoclonal anti-TNFα antibody fragment) is the most efficacious compound in inductionand maintenance therapy of active and fistulizing Crohn's disease, being at present the only biological compoundapproved for therapy, but with the limit of the immunogenicity; CDP-571 (a humanized anti-TNFα antibody) andCDP-870 (a PEGylated anti-TNFα antibody) are less immunogenic, showed some efficacy in induction therapy inCrohn’s disease but a rapid loss of response in maintenance therapy. Etanercept and onercept (soluble humanrecombinant TNFα receptors fusion proteins) seem not to be efficacious in Crohn's disease demonstrating noclass-effect for anti-TNFα compounds. In preliminary study, adalimumab (an IgG1 humanized monoclonal anti-TNFα antibody) offers good perspective of efficacy and safety also in infliximab-resistant or allergic patients.Inhibition of lymphocyte trafficking to the gut, through anti-adhesion molecules specific therapies (natalizumab,MLN-02, alicaforsen), has shown promising results: unfortunately, natalizumab, the most effective drug of thisclass, has recently been suspected to favour serious neurological complications. Other biologic therapies are underevaluation but at present seem to be less promising than infliximab; they consist of antiinflammatory cytokines,inhibitors of proinflammatory cytokines, hormones and growth factors: anti-IL12-antibody, interferonα,interferonβ,G-CSF, GM-CSF, EGF, growth hormone, anti-interferonγ, anti-IL-18, anti-IL-2-receptor and anti-CD3 antibodies. The evaluation of other biological drugs has been suspended for severe side effects as happened foranti-CD40L antibody causing thromboembolism and anti-CD4 antibody causing ly.mphopenia. Other compoundsas IL-10 and IL-11 have been proven to be ineffective even if an oral formulation of IL-11 is under evaluation.Among the MAP kinases inhibitors BIRB-796 and RDP58 showed to be ineffective while CNI-1493 is underevaluation. The effort in identifying specific patients features predicting therapy response and the possible combination ofdifferent biological therapies represent undoubtedly a very promising perspective. Aim of this article is to reviewthe biological compounds and their efficacy in IBD.

Pharmacologic support of the failing neonatal heart to maintain cardiac output, which is vital for sufficient end organ perfusion, is a challenging task for the pediatric intensivist, especially since strategies which have been proven to be effective in adults cannot necessarily be extrapolated to neonates. The unique biochemical properties and structure of the neonatal heart, including the increased non-contractile tissue mass, a lower responsiveness to beta adrenergic agents and the heart rate dependent cardiac output with a limited ability toincrease stroke volume, favor some of the new inotropes of the Ca+ sensitizer family. Focusing on the after loadreduction, inodilators as phosphodiesterase inhibitors and human brain natriuretic peptide offer treatment optionsfor the neonatal myocardium. Additionally, thyroxine and steroids have been investigated in neonates with lowcardiac output after surgery for congenital heart disease. Gene therapy, in particular cardiac-selective gene transfer,might offer perspectives for future support for the neonatal heart. This text reviews some of the most recentpharmacologic strategies targeting the failing myocardium in the critically ill newborn and infant

A number of conjugates tend to self-associate in a transient or permanent fashion and this has formed the basisof considerable intense scientific and commercial investigation over recent years. This article considers a variety ofstrategic formulations, their flaws and advantages. Working practices and groundbreaking developmental activities withinthe sphere of self-assembling drug conjugates are also reviewed.

NMDA receptors are linked to neuronal loss in stroke and neurodegeneration because their activation can triggerexcitotoxic Ca2+ dysregulation. Accordingly, NMDA receptor antagonists are neuroprotective, providing a rationale fortheir clinical application. However, side effects often outweigh benefits. Herein we highlight structural properties inreceptors that are used in drug development.

There are two types of bacterial communication systems, those in which the signal produced by bacteria isdirected only at other organisms, and those where the signal is detected by others and self. The latter is involved inadaptation to the environment. The adaptation signals are autoinducers, the response is population density-dependent andhas been termed "quorum sensing". Our current knowledge of bacterial signaling systems indicates that Gram positivebacteria use small peptides for both types of signaling, whereas Gram negative organisms use homoserine lactones asautoinducers. Gram- negative bacteria internalize the signals which act upon an intracellular receptor. Gram-positivebacteria use the signals as ligands for an extracellular receptor of a two-component signaling system. Inhibitors of quorumsensing compounds for both Gram positive and Gram negative bacteria are being explored. Signal inhibitors could bepotentially effective in impeding biofilm formation, which might prolong the utility of the currently available antibioticsin this era of antibiotic resistance. In this review, we will explore both bacteria-host and bacteria-bacteria communicationsystems, with an emphasis on inhibitors of these systems both natural and synthetic.

We have focused on cyclooxygenase, the key enzyme in prostaglandin synthesis, from our basic knowledge regarding the enzyme, to its clinical application in the field of oncology. We will present evidence that this enzyme is intimately associated with carcinogenesis, invasion, metastasis, and the response of tumors to current therapeutic modalities in a variety of human malignancies. We will also discuss the applications of cyclooxygenase inhibitors tochemoprevention and to the sensitization of tumors to conventional anti-cancer therapies.

It is known that the renin-angiotensin system (RAS) plays a fundamental role not only as a vasoconstrictor incontrolling blood pressure and electrolyte/fluid homeostasis, but also as a mitogenic factor through the Ang-II type-1(AT1) receptor in smooth muscle cells and cardiac myocytes. Angiotensin II (Ang-II) is indeed thought to be a growthfactor, and Ang-II receptor blockers (ARBs), a class of antihypertensive agent, suppress signal transduction pathwaysmediated by several growth factors or cytokines, through the AT1 receptor. There is increasing evidence that the RAS isimplicated in the development of various cancers. We previously demonstrated that ARBs have the potential to inhibit thegrowth of prostate cancer cells and tumors through the AT1 receptor. This review highlights the possibility of ARBs asnovel agents for prostate cancer as well as other cancers, and reviews the literature on this area.