Current Medicinal Chemistry - Volume 17, Issue 4, 2010

Reverse transcription of the viral single-stranded (+) RNA genome into double-stranded DNA is an essential step in the human immunodeficiency virus' (HIV) life-cycle. Although several viral proteins are involved in the regulation and/or efficiency of reverse transcription, the process of retroviral DNA synthesis is entirely dependent on the enzymatic activities of the retroviral reverse transcriptase enzyme (RT). Due to its crucial role in the HIV life-cycle, RT is a primary target for anti-HIV drug development. Nonetheless, drug resistance is the major problem affecting the clinical efficacy of antiretroviral agents. Incomplete pharmacological pressure represents the logical cause and not the consequence of different mutation pathways in RT associated with approved inhibitors resistance. In this review we have analyzed RT Protein Data Bank (PDB) models using our innovative computational approach “GRID Based Pharmacophore Model” (GBPM). This method was applied to clinically relevant RT conserved residues found in a large cohort of HAART treated patients. The PDB entries have been selected among the unbound and the complexed models with DNA and/or inhibitors. Such an approach has revealed itself useful to highlight the mutation effects in the drug-RT recognition as well as in the heterodimer stabilization of the enzyme. Most of the clinical and biochemical evidences already reported in the literature have been rationalized at molecular level via the GBPM computational approach. A definite future application of this method will be the identification of conserved regions of critical macromolecules, such as the HIV-1 RT, to be targeted for the development of innovative therapeutic agents.

The biological activity of peroxisome proliferators (PPs) is mediated by a class of receptors, known as PPARs (PP-Activated Receptor), belonging to the nuclear receptor superfamily. Upon ligand binding, PPARs dimerize with retinoid receptors, translocate to the nucleus, recognize specific PP-responsive elements on DNA and transactivate a number of genes. Several processes are regulated by PPARs, such as mitochondrial and peroxisomal fatty acid uptake and β- oxidation, inflammation, intracellular lipid trafficking, cell proliferation and death. In addition, PPARs have been proposed to act as tumor suppressors or as tumor promoters, depending on the circumstances. In particular, PPs have been extensively studied for their hepatocarcinogenic action in rodents, most often ascribed to their antiapoptotic action. Recent evidence, however, has been provided about the antiproliferative, proapoptotic, and differentiation-promoting activities displayed by PPAR ligands. The present review will focus on the cytotoxic effects exerted by several PPs, among which clofibrate, on different types of tumor cells, with particular reference to the mechanisms of cell death and to their relevance to cancer induction and progression.

Compound lipophilicity connected to ADME(T)a has great importance in drug development and it has to be evaluated by the generally used drug developmental process. In addition to the importance of lipophilicity in ADMET, recently it has been reported that lipophilicity of small molecules correlates with their antiproliferative activity because of certain specific hydrophobic and lipophilic interactions. Due to the complexity of ADME(T) parameters an efficient and fast method is needed to characterize the many promising candidate lead molecules as a preselection in order not to be rejected from the latter phase of drug development. In the present paper we provide an overview of the importance of lipophilicity of drug candidates for biological action and for ADME(T) and describe a novel approach for drug-likeness characterization of a molecular library using correlation study between lipophilicity and biological activity. Lipophilicity and molecular characteristics have been measured, predicted and optimized for a diverse library from which the best members have been selected to describe their biological, chemical and drug-likeness properties. Molecules were selected from the family of α,β-unsaturated ketones and thorough HPLC characterization for lipophilicity and morphological, antiproliferative and flow cytometric studies were carried out on them. Based on the results 17 member isochromanone library including E and Z geometric isomers were selected for further characterization. In this focused library linear correlation has been found between the calculated and measured lipophilicity and significant parabolic correlation was found between the antiproliferative effect and lipophilicity. Using our efficient and fast method, from a diverse library, we identified an outstandingly effective inhibitor of A431 tumour cell growth via a PARPa cleavage dependent apoptosis. In summary the optimized HPLC analyses of lipophilicity combined with the cell-culture assay, introduced above, resulted in the determination of an optimal lipophilicity range. This optimized lipophilicity range should be used in designing novel antiproliferative compounds.

The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is one of the most studied neurotransmitters in the central nervous system. It acts through the activation of at least fourteen 5-HT receptor subtypes. Over the last two decades, high attention was devoted to the 5-HT3 and 5-HT4 receptors due to their colocalization in the gastrointestinal tract and because their ligands are useful in the treatment of intestinal serotonergic system dysfunctions. The focus of this review is to discuss the literature concerning recent advances on 5-HT3R and 5-HT4R ligands and their structure-activity relationships from a medicinal chemistry perspective. During the last few years, new and significant progresses have been made in the field of novel potent and selective ligands, mixed ligands, agonists, partial agonists, and antagonists, and a number of patents have been filed. Furthermore several ligands targeting the 5-HT3R and 5-HT4R have been proposed for novel therapeutic indications such as the treatment of various psychiatric disorders.

Acute heart failure syndromes (AHFS) enclose a broad spectrum of conditions with different clinical presentations, heart failure history, pathophysiology, prognosis and treatment. AHFS represent a major public health problem because of their high prevalence, high rates of mortality and readmissions and significant healthcare costs, and a therapeutic challenge for the clinicians because management strategies vary markedly. Traditionally used drugs for the treatment of AHFS, including diuretics, vasodilators and positive inotropics, improve clinical signs and symptoms as well as hemodynamics, but present important limitations, as they fail to reduce and may even increase in-hospital and postdischarge mortality, especially in patients with coronary artery disease. Thus, we need new pharmacological agents to not only improve signs and symptoms and cardiac performance, but also improve both short- and long-term outcomes (hospitalizations/ survival). In the last decade, significant efforts have been made to identify new therapeutic targets involved in the genesis/progression of AHFS and to develop new therapeutic strategies that may safely improve outcomes. As a result, several new families of drugs have been developed and are currently studied in experimental models and in Phase II and III clinical trials, in an attempt to define their efficacy and safety profiles as well as their precise role in the treatment of AHFS patients. This review firstly analyzes the main clinical applications and limitations of conventional drugs, and then focuses on the mechanisms of action and effects of recently approved drugs and of new investigational agents on signs, symptoms, hemodynamics and outcomes in AHFS patients.