Mini Reviews in Medicinal Chemistry - Volume 8, Issue 11, 2008

Advanced drug delivery systems try to adjust the site and/or the rate of the release to the physiological conditions of the patient, to the progression of the illness, or to the circadian rhythms. Being different from classical preprogrammed controlled release dosage forms, the new devices aim to provide the drug release profile best for the needs of each patient. Intelligent drug delivery systems are mostly based on stimuli-responsive polymers which sense a change in a specific variable and activate the delivery; this phenomenon being reversible. This review reports on recent advances in the development of open-loop and closed-loop control systems based on stimuli-responsive polymers and their application in the drug delivery field as pulsatile and self-regulated devices. The aim of this review is to describe the most recent advances in the development of intelligent micelles and hydrogels which are sensitive to pH, specific molecules (with a mention to the molecular imprinting), temperature, irradiation or electric field, and the applications of which these mechanisms are intended.

There has been considerable in vivo evidence that chemokine receptor CXCR4 and its endogenous ligand CXCL12 modulate some important physiological and pathophysiological processes, including cancer metastasis, angiogenesis, invasion, growth and progression. In this review we elucidate key aspects of CXCL12-CXCR4 signaling system with emphasis on peptide-based and small-molecule CXCR4 inhibitors.

Depsipeptides are a large group of natural products produced by fungi, actinomycetes, cyanobacteria, higher plants and marine organisms. This family of compounds is known to exhibit a wide range of biological activities, and thanks to the progress of isolation techniques and the advances of methods for structure determination, the numbers of depsipeptides having both unique structures and attractive biological activities are increasing. Many of these compounds have shown a wide range of biological activities, and some are in clinical use or have entered human clinical trials as antibiotic or anticancer agents. However, only a handful of them have been evaluated for their antimalarial activity. This paper aims to review the recent advances in depsipeptides as potential antimalarial compounds.

Transcription factors are an important group of proteins. Changes in expression or activity of transcription factors result in diverse and manifold effects on the whole transcriptome of the cell. Therefore transcription factors are of special interest in physiological as well as pathological processes particularly tumour development and progression. In this review we focus on Ets-1, the prototype of the ETS family of transcription factors. ETS family members play important roles in development, differentiation and proliferation of cells in general and they are involved in apoptosis and tissue remodelling as well. Most of them are downstream nuclear targets of Ras-MAP kinase signalling and the deregulation of ets genes results in malignant transformation of different cells. Several ets genes are rearranged in human leukaemia, Ewing tumours and prostate cancer to produce chimeric oncoproteins. Furthermore, an aberrant expression of several ets genes is often observed in various types of human malignant tumours. With regard to the involvement of some ETS transcription factors, especially Ets-1, in malignant transformation and tumour progression (including invasion, metastasis and neoangiogenesis) through transactivation of cancer related genes, they are potential molecular targets for selective cancer therapy. In this review we focus on the roles of Ets-1 for tumour development and progression with special emphasis on tumour vascularization and invasion. We then discuss specific strategies for Ets-1 inhibition as a potential tool for cancer treatment.

Numerous numbers of biologically active agents have been identified for their diverse therapeutic functions. Detailed investigations of phytochemicals for antiviral activities have assumed greater importance in the last few decades. A wide variety of active phytochemicals, including the flavonoids, terpenoids, organosulfur compounds, limonoids, lignans, sulphides, polyphenolics, coumarins, saponins, chlorophyllins, furyl compounds, alkaloids, polyines, thiophenes, proteins and peptides have been found to have therapeutic applications against different genetically and functionally diverse viruses. The antiviral mechanism of these agents may be explained on basis of their antioxidant activities, scavenging capacities, inhibiting DNA, RNA synthesis, inhibition of the viral entry, or inhibiting the viral reproduction etc. Large number candidate substances such as phytochemicals and their synthetic derivatives have been identified by a combination of in vitro and in vivo studies in different biological assays. In this article we have made attempts to extensively review and provide comprehensive description of different phyto-antiviral agents. We have examined the recent developments in the field of plant derived antiviral agents. The major advances in the field of viral interactions in various biological assays have been summarized. In addition sources of origin, major viral studies mechanistic action and phase trials of various phytoantiviral agents have been included in the review.

Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) belongs to highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. The antidotal treatment of tabun acute poisonings still represents a serious problem and the development of new, more effective AChE reactivators to achieve the satisfactorily effective antidotal treatment of acute poisonings with tabun still represents very important goal. Since 2003, we have prepared around 200 new AChE reactivators. Their potency to reactivate tabun-inhibited acetylcholinesterase has been subsequently evaluated using our in vitro screening test. Afterwards, promising compounds were selected and kinetic parameters and reactivation constants were determined. Then, the best reactivators were subjected to the in vivo studies (toxicity test, the evaluation of therapeutic, reactivating and neuroprotective efficacy) and their potency to counteract the acute toxicity of tabun is compared to the therapeutic, reactivating and neuroprotective efficacy of commonly used oximes - obidoxime and the oxime HI-6. According to the results obtained, the newly synthesized oxime K075 showed the highest potency to reduce tabuninduced acute lethal toxicity while the therapeutic potency of obidoxime and the oxime HI-6 was significantly lower. The therapeutic efficacy of oximes studied corresponds to their reactivating efficacy in vivo as well as in vitro. The potency of all newly synthesized oximes to reactivate tabun-inhibited AChE is comparable with obidoxime with the exception of K074 that is significantly more efficacious in the brain. In addition, all newly synthesized oximes combined with atropine seem to be effective antidotes for a decrease in tabun-induced acute neurotoxicity. While the neuroprotective efficacy of obidoxime in combination with atropine is similar to the potency of newly synthesized oximes, the ability of the oxime HI-6 combined with atropine to counteract tabun-induced acute neurotoxicity is significantly lower. Due to their therapeutic, reactivating and neuroprotective efficacy, all newly synthesized oximes appear to be suitable oximes for the antidotal treatment of acute tabun poisonings.

Chronically-elevated blood glucose initiates a harmful series of processes in which toxic reactive species play crucial roles. Oxidative as well as nitro-oxidative stress is harmful for virtually all biomolecules including lipids, proteins and DNA. Such pathophysiologic mechanisms eventually results in cellular dysfunction, apoptosis or necrosis. Melatonin is a multifunctional indolamine which counteracts several pathophysiologic steps and displays significant beneficial effects against hyperglycemia-induced cellular toxicity. These are related to melatonin's antioxidative, anti-inflammatory and possibly epigenetic regulatory properties. Current knowledge encourages using this non-toxic indolamine either as a sole treatment or in conjunction with other treatments for inhibition of the biohazards of hyperglycemia.

The structures of caspases reveal the mechanism of binding for non-peptide and protein inhibitors, and have been applied in the design of agents that either inhibit or activate caspases to control cell death in diverse diseases. Decreased cell death is desirable for treatment of stroke, nerve crush injury, myocardial infarction, neuromuscular and neurodegenerative diseases and several non-peptide caspase inhibitors have been developed. In contrast, activation of cell death would be advantageous in cancer therapy, and the strategy is to block the binding of inhibitory proteins to caspases. Recent preclinical studies are described.

G-quadruplex structures are promising targets for design of cancer drugs with high selectivity and low toxicity. This review provides an update of the progress made over the last few years in the design of selective G-quadruplex ligands, and a comprehensive summary of the major design strategies and structural characteristics.