Mini Reviews in Medicinal Chemistry - Volume 11, Issue 1, 2011

Classic chemotherapy has little or no specificity for cancer cells, normally resulting in low accumulation at the tumor region (inefficacy), and in severe side effects (toxicity). This challenge has resulted in the development of several delivery strategies for chemotherapy agents to improve their concentration at the tumor site, simultaneously increasing their anticancer efficacy, while reducing the associated adverse systemic effects. In this work, the potential of drug delivery strategies involving the use of nanocarriers for controlling the biodistribution of antitumor drugs is deeply revised: passive targeting (through the enhanced permeability and retention effect, EPR effect) and active targeting (including stimuli-sensitive carriers and ligand-mediated delivery). Special attention will be also focussed on the recent approaches for overcoming multi-drug resistance. Finally, a general view of the problem of “nanotoxicity” in cancer treatment is also given.

Vascular endothelial growth factor receptor (VEGFR) is an important receptor tyrosine kinase (RTK) in the induction of angiogenesis. Abnormal activation of VEGFR leads to several disorders including cancer. Nowadays, inhibition of VEGFR kinase has been one of the most powerful clinical strategies in cancer treatment and great efforts to design and synthesize small molecular VEGFR inhibitors for cancer research have been made in recent years. This review highlights the major progress and development of them, including their structure and pharmacophore features, biological activities and structure-activity relationships (SAR). Special attentions are paid to the compounds available in market or in advanced clinical stages.

Plants contain major glycoglycerolipids, such as monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG) and sulfoquinovosyl diacylglycerol (SQDG), in the chloroplast membrane. The bioactivities of purified MGDG, DGDG and SQDG from spinach have been investigated extensively. MGDG and SQDG have been shown to inhibit the activities of mammalian DNA polymerases, but DGDG has no such inhibitory effect. The effect of these glycoglycerolipids on cancer cells, angiogenesis and solid tumor growth might be mediated via their inhibition of replicative DNA polymerase activities. On the basis of these findings, we discuss the mode of action of plant chloroplast glycoglycerolipids as anti-cancer therapeutic agents.

In this article we review our work over the years on carbohydrates and carbohydrate mimetics and their applications in medicinal chemistry. In the first part of the review innovative synthetic methods, such as the chemoselective glycosylation method originally developed by our group and its applications to the synthesis of neoglycoconjugates (neoglycopeptides, oligosaccharide mimetics, neoglycolipids, etc…) will be presented. The high density of functional groups (hydroxyls) on the monosaccharides and the structural role of sugars forming the core of complex glycans in scaffolding and orienting the external sugar units for the interaction with receptors, inspired us and others to use sugars as scaffolds for the construction of pharmacologically active compounds. In the second part of this review, we will present some examples of bioactive and pharmacologically active compounds obtained by decorating monosaccharide scaffolds with pharmacophore groups. Sugar-derived protein ligands were also used as chemical probes to study the interaction of their target with other proteins in the cell. In this context, sugar mimetics and sugar-derived compounds have been employed as tools for exploring biology according to the “chemical genetic” approach.

In the current review, we discuss the role of NF-κB and JAK/STAT signaling pathways and their small molecule regulators in the therapy of inflammatory diseases. Considering potential harmful effects directly assigned to the COX-2 inhibition, novel therapeutically-relevant biological targets such as NF-κB and JAK/STAT signaling pathways have received a growing attention. Here we summarize recent progress in the identification and development of novel, clinically approved or evaluated small molecule regulators of these signaling cascades as promising anti-inflammatory therapeutics. In addition, we illustrate key structural modifications and bioisosteric transformations among these inhibitors to provide a helpful basis for further development of novel small molecule anti-inflammatory agents.

A number of studies have identified differential kavalactone activity against a variety of molecular targets, including P glycoprotein (Pgp), platelet monoamine oxidase (MAO-B), transcription factor binding domains, pregnane X (PXR) and GABA receptors, and cytochrome P450 and cyclo-oxygenase (COX) enzymes. The molecular structure of the kavalactones possesses a pharmacophore for several of these targets. In most cases, conformational stability is more significant than the substituents present. The analysis of these pharmacophores provides important insights for future medicinal chemistry-based approaches to kavalactone-type drugs.

Emergence of severe viral infections in recent years and limited availability of antiviral chemotherapeutic agents for prevention and treatment of these infections are among the most common causes of human illness and death. Therefore, there is an urgent need to develop antiviral drugs that have a potentially critical role in the prevention and treatment of various fatal and debilitating viral infections. Triazole derivatives occupy a pivotal position in modern medicinal chemistry and several have found applications as medicines. A large volume of research has been carried out on triazole and their derivatives for antiviral activity and pharmacological importance of this scaffold has been well established. This review is primarily addressed to description of the recent advances in the synthesis and evaluation of triazole derivatives as antiviral agents which may facilitate the development of more potent and effective antiviral agents.

Glucagon-like peptide-1 (GLP-1) is involved in satiety control and glucose homeostasis. Besides, GLP-1 has cardiovascular effects. In experimental models, GLP-1 increases cardiac output and exerts a direct vasodilatory effect. In animals with dilated cardiomyopathy GLP-1 improves left ventricular performance. Human data demonstrated that GLP-1 reduces arterial blood pressure, improves endothelial function in individuals with diabetes and left ventricular function in patients with heart failure. Administration of GLP-1 increases ejection fraction in acute myocardial infraction and reduces ischemia-reperfusion myocardial injury. Although more research is needed, these data suggest that GLP-1 may be used with promising results in patients with heart failure, acute myocardial infarction and revascularization procedures in addition to the standard therapy.