Mini Reviews in Medicinal Chemistry - Volume 10, Issue 14, 2010

Histamine is a biomolecular compound located in various parts of body. It participated in various important cellular activities associated with allergy and asthma. This magic bio-molecule is directly and indirectly involved in various biochemical reactions through G-protein couple receptors. Various histamine receptors and their unexplored biochemical activities attracted many biologists in last few decades. A surprising discovery of histamine H4 receptor was done when scientists worked on histamine H3 receptor in brain cells. The binding pocket of histamine H4 differs by transmembrane domains (TM3, TM5 and TM6) from histamine H3-sub type. In this review, we enlightened various functions of histamine H4 receptor and use of histamine H4 receptor antagonists in autoimmune diseases, allergic responses, inflammatory responses, and in superoxide generation which are helpful to establish H4 receptor antagonists as newer anti histamines.

Host intracellular iron has been recognized as an important cofactor in induction of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidative burst as antimicrobial defense mechanism. It is plausible that iron chelator directly inactivates NADPH oxidase by chelating the active site heme iron of flavocytochrome b558 thus blocking the transfer of electrons from NADPH to oxygen and its reduction to superoxide anion. Thus, altering the equilibrium of intracellular iron could influence the course of infection to the enhancement of the pathogen with regard to oxidative stress.

A large number of therapeutic medications have undesirable properties that may generate pharmacological, pharmaceutical, or pharmacokinetic barriers in clinical drug applications. Metabolism of drugs by Phase-I & Phase-II metabolic pathways for possibility of active metabolites, which could in turn useful for rational designing of bioprecursor prodrugs of the active principle of interest. This review summarizes various approaches & development of drugs, namely bioprecursor prodrugs and active metabolites related to bioprecursor prodrugs.

Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus type 1 (HIV-1) infection, is still one of the most challenging diseases of the early 21st century. Reverse transcriptase (RT), protease (PR) and integrase (IN) are three key enzymes of HIV-1. Despite the shortcomings of chemical drugs such as toxicity, lack of curative and multiple effects, the search for more and better anti-HIV agents has been focused on natural products. Many natural products have been shown to possess promising activities that could assist in the prevention and amelioration of the disease. Most of these natural anti-HIV agents have other medicinal values as well, which afford them further prospective as novel lead compounds for the development of new drugs. These natural products can deal with both the virus and the various disorders that are caused by HIV. In this review, natural inhibitors of RT, PR and IN have been found to be classified and the relationship between structure and inhibitory activity is discussed.

The productions and applications of various microbial exopolysaccharides have been under intensive researches over the past few decades. Some of these exopolysaccharides are commercial available and some are currently under intensive development; they include ionic heteropolysaccharide and neutral homopolysaccharide. These extracellular polymers constitute a structurally diverse class of biological macromolecules with a wide range of physiochemical properties which are the basis for the different applications in the broad fields of pharmacy and medicine. They have found applications in such diverse biomedical fields as ophthalmology, orthopedic surgery, tissue engineering, implantation of medical devices and artificial organs, prostheses, dentistry, bone repair and drug delivery.

Endometrial Cancer is the most frequent tumor in western world nations, with 142,000 new cases each year and 42,000 casualties. This form of cancer typically affects women between 55 and 65 years of age, and ranks fourth among female tumors. Endogenous predisposing conditions to endometrial cancer development are: late menopause, early menarche and hyperestrogenism, while hormone replacement therapy, obesity, alcohol, diabetes, and a diet rich in animal fats as well as chronic liver disease, are the exogenous factors. This tumor may also have an hereditary predisposition, as in the Lynch Syndrome or in HNPCC (Hereditary NonPolyposis Colorectal Cancer), since genetic modifications induced by the “MisMatch Repair” genes lead to a tumoral development susceptibility, not only in the colon. The phenotypical consequences of these genetic modifications may be found in the microsatellite instability (MSI) and in the loss of heterozygosity (LOH), which generate the replication errors in positive phenotypes repeats. These express the incapability to repair short nucleotide insertions or deletions, generated by a wrong DNA replication. Due to such genetic modifications, new allelic variants arise in the endometrial tissue, confirming the high degree of this genetic disorder. Recent studies showed that the MSI and LOH in endometrial cells may be associated with the possible loss in the expression of cellular control and with the possible degeneration of the cell growth phenomenon. There is also a possibility of utilizing these new genetic markers in the endometrial mucosa to study these tissues and to detect any possible neoplastic transformations, thanks to Genomics.

The renin angiotensin system (RAS) plays an important role in regulation of blood pressure and fluidelectrolyte homeostasis. The renin-angiotensin system consists of a cascade of enzymatic reactions producing angiotensin II (Ang II). Ang II is a vasoconstrictive peptide hormone that exerts a wide variety of physiological actions on cardiovascular, renal, endocrine and central nervous systems. The RAS can be inhibited at various points to control pathogenesis of hypertension. Renin inhibitors and angiotensin-converting enzyme (ACE) inhibitors were the earliest RAS blocking agents. A relatively new class of compounds known as Ang II receptor antagonists (SARTANs) is developed for the treatment of hypertension. They exert their action by blocking the binding of Ang II on AT1 receptor. Angiotensin converting enzyme (ACE) inhibitors are associated with incident of side effects such as cough and angioedema while clinical trials with Ang II receptor antagonists have confirmed that these drugs are safe and efficacious for the treatment of hypertension. Based upon the understanding of molecular interaction of Ang II receptor antagonists with AT1 receptor some of the common structural features have been identified, such as a heterocyclic (nitrogen atom) ring system, an alkyl side chain and an acidic tetrazole group. Research efforts for development of new molecules with similar structural features have led to the discovery of various non-peptidic Ang II receptor antagonists with different substituted heterocylic such as imidazole (losartan) and benzimidazole (candesartan and telmisaratn). In this study we have critically reviewed various benzimidazole substituted compounds as Ang II- AT1 receptor antagonists and explored other potential clinical uses for this class of compounds.

Somatic genetic and epigenetic alterations have been suggested to be crucially involved in development and progression of cancers including prostate cancer (PCa). Epigenetic alterations such as chemical modification of chromatin associated proteins and DNA methylation can largely affect gene expression that may be important for early normal organ development, and also produces favorable conditions for cancer cell formation, growth, and survival. Aberrant DNA methylation (hyper- or hypo-methylation) may lead to chromosomal instability, and transcriptional gene silencing for tumor suppressors or overexpression for oncogenes. Vitamin Bs play important roles in one carbon metabolism that provides critical metabolites for DNA methylation, DNA repair and nucleic acid synthesis. Nutrition uptake and circulating levels of these vitamin Bs as well as genetic polymorphisms of related key enzymes in the one carbon metabolism pathway may govern bioavailability of the metabolites, and therefore to affect the phenotypic changes (e.g., cellular malignancy) via genetic and epigenetic alterations. This article will summarize recent new findings from laboratory, epidemiological or clinical trial studies regarding influence of vitamin B and one carbon metabolism on PCa development or progression.

Chemiluminescence has traditionally been used to study the nature of the oxidative bactericidal mechanisms of neutrophils and monocytes, intrinsic defects of abnormally functioning neutrophils or monocytes and cell activation. During the last ten years, Chemiluminescence has been applied in a wide variety of techniques, including immunoassays, protein blotting and toxicological and pharmacological tests (e.g. after exposure to antibiotic or immunomodulators agents, such as adjuvants and cytotoxic drugs). In this review, we discuss some promising clinical applications of Chemiluminescence in clinical immunology for the study of autoimmune diseases, inflammatory responses, endocrine disorders, immunodeficient states, mucosal immune responses against drugs and pathogens and host responses against tumors and infections. Further, we review the numerous advantages of Chemiluminescence-based methods over other methods to assay the same endpoints, which facilitate their use in the current practice of clinical immunology.