Mini Reviews in Medicinal Chemistry - Volume 6, Issue 4, 2006

Coumarins, an old class of compounds, are naturally occurring benzopyrene derivatives. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogs. The pharmacological and biochemical properties and therapeutic applications of simple coumarins depend upon the pattern of substitution. Coumarins have attracted intense interest in recent years because of their diverse pharmacological properties. Among these properties, their antioxidant effects were extensively examined. In this review, plant derived coumarins and their synthetic analogs will be systematically evaluated based on their plant origin, structure-activity relationship and antioxidant efficacy. Owing their diverse effects and inconclusive results from different in vitro studies, the mechanism of their action has not yet been fully understood and the correlation of effects with chemical structure is not conclusive at the moment. It is the objective of this review will be to summarize experimental data for different coumarins used as antioxidant agents, because promising data have been reported for a series of these agents. In addition, their ability to bind metal ions represents an additional means of modulating their pharmacological responses.

A major recent focus of quinolone antibacterials has been the development of agents with enhanced activity against Gram-positive bacteria. The extensive research efforts have enabled a better definition of the structural features of quinolones that offer the best combination of clinical efficacy and reduced resistance selection in Gram-positive bacteria. This review considers the structural features of new quinolones and relationship to antibacterial activity against Gram-positive bacteria, while trying to position them in the context of recent and possible future advances based on an understanding of their chemical structure and how these impact on target specificity, avoidance of efflux and prevention of emergence of quinolone-resistant mutants in Gram-positive bacteria.

Novel anti-cancer treatments use knowledge about the underlying biology of the tumor to find suitable molecular targets. The recent years have seen great advances in understanding the biology of melanoma. In the current review we discuss the most promising molecular targets for melanoma and suggest possible strategies for overcoming resistance.

Ifosfamide (IFO), an oxazaphosphorine-type anticancer alkylating agent, was found to be particularly useful in the treatment of a wide variety of neoplasm in adults and children. IFO is a positional isomer of cyclophosphamide (CPA) and was introduced into clinical practice in the '80s and has recently attracted much attention. Therapeutic application of high-dose IFO is limited by several side-effects; among them neurotoxicity and nephrotoxicity give the greatest concern. The presence of these side-effects is likely to be connected with the metabolism of this drug. In recent years there have been many studies aiming better understanding metabolism of this drug, employing new therapeutic approaches and preparing new analogs.

Genistein, one of the predominant soy isoflavones, has been shown to compete with 17 β-estradiol for estrogen receptor binding because of its structural similarity, resulting in agonistic or antagonistic activity. It causes inhibition of cell growth in breast and prostate cancers in vivo and in vitro. From gene expression profiles, genistein has been found to regulate the genes that are critical for the control of cell proliferation, cell cycle, apoptosis, oncogenesis, transcription regulation, and cell signal transduction pathways. It has been reported that genistein induces apoptosis and inhibits activation of NF-βB and Akt signaling pathways, both of which are known to maintain a balance between cell survival and apoptosis. Recently, we found that genistein sensitized cancer cells to apoptosis induced by chemotherapeutic agents including docetaxel, gemcitabine and cisplatin through inactivation of NF-βB in multiple cancer cell lines. To enhance the anti-cancer activity of genistein, we have synthesized structurally-modified derivatives of isoflavone based on the structural requirements for optimal anti-cancer effect. We found that these synthetic derivatives of isoflavone exerted higher anti-cancer activity with lower IC50. These derivatives of isoflavone also induced more apoptosis compared to genistein. These results suggest that genistein and synthetic structurally-modified derivatives of isoflavone may be promising agents for cancer chemoprevention and therapy either alone or in combination with existing chemotherapeutic agents.

Reactive oxygen species can induce several biological processes by stimulating signal transduction components such as cytosolic free calcium concentration. The physiological significance of the role of biological oxidants in the regulation of calcium signalling pathway as well as the mechanisms of the oxidantstimulation of signal transduction are discussed in this review.

The pharmacokinetics of corticosteroids provides a large set of mathematical models which led to analyse many kinetic profiles corresponding to many clinical and/or physiological situations. In this paper, we present a review on the usefulness, advantages and limits of such models which could find a large application in medicinal chemistry.

Neuraminidase (NA) is the major surface glycoprotein of the influenza virus. It has been considered a suitable target for designing agents against influenza viruses. Rational drug design of NA inhibitors is now in the clinic and is effective for the treatment of influenza. Recently, research of structure-based NA inhibitors is becoming an interesting field, leading to a breakthrough in the control of influenza. Here we review a series of neuraminidase inhibitors and the recent progress in this field.

Computational methods for predicting compounds of specific pharmacodynamic, pharmacokinetic, or toxicological property are useful for facilitating drug discovery and drug safety evaluation. The quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) methods are the most successfully used statistical learning methods for predicting compounds of specific property. More recently, other statistical learning methods such as neural networks and support vector machines have been explored for predicting compounds of higher structural diversity than those covered by QSAR and QSPR. These methods have shown promising potential in a number of studies. This article is intended to review the strategies, current progresses and underlying difficulties in using statistical learning methods for predicting compounds of specific property. It also evaluates algorithms commonly used for representing structural and physicochemical properties of compounds.

The unique biological properties of Geminin, particularly as an inhibitor of DNA replication initiation, have been recognized, and this has prompted a number of investigations into this molecule to explore its potential therapeutic as well as diagnostic usefulness. This review summarizes the possibility of Geminin serving as a new molecular target in the development of new anticancer drugs.

CC chemokine receptor (CCR) 8, which is expressed on Th2 cells and eosinophils, has been implicated in allergic diseases. This review represents an overview of the functional roles of CCR8 in the pathogenesis of eosinophilic inflammation and debates the potential of recently developed CCR8 antagonists to treat allergic disorders.

Cardiovascular diseases are still the main cause of morbidity and mortality in the world. Anti-platelet drugs have found clinical application in the secondary prevention of vascular events including acute myocardial infarction, stroke and cardiovascular death. In the present review, we have developed sixteen quantitative structure-activity relationships (QSAR) for different sets of compounds that are X-phenols (I), Xcatechols (II ), caffeic acid amides (III), X-alcohols (IV), 1,4-naphthoquinones (V), tetrahydronaphthalenes (VI), phenoxyacetaldehyde guanylhydrazones (VII), pyrrolobenzylisoquinolines (VIII) and phosphonic acids (IX) with respect to their anti-platelet activities. QSAR results have shown that the anti-platelet activities of these compounds are largely dependent not only on their hydrophobicity, but also on the influence of their molar refractivity.

Human serum albumin (HSA), the most prominent protein in plasma, is best known for its extraordinary ligand binding capacity. The three homologous domains of HSA (labeled I, II, and III), each in turn composed of two subdomains (named A and B), give rise to the three-dimensional structure of HSA. This flexible structural organization allows the protein structure to adapt to a variety of ligands. As conformational adaptability of HSA extends well beyond the immediate vicinity of the binding site(s), cooperativity and allosteric modulation arise among binding sites; this makes HSA similar to a multimeric protein. Although kinetic and thermodynamic parameters for ligand binding to HSA calculated by quantitative structure-activity relationship models are in excellent agreement with those obtained in vitro, cooperative and allosteric equilibria between different binding sites and competition between drugs or between drugs and endogenous ligands make difficult the interpretation of HSA binding properties in vivo. Binding of exogenous and endogenous ligands to HSA appears to be relevant in drug therapy and management. Here, the allosteric modulation of drug binding to HSA is briefly reviewed.