Current Medicinal Chemistry - Volume 16, Issue 19, 2009

Platinum drugs are widely used in antitumour therapy and are a cornerstone of the treatment of different solid tumours. The pharmacological interest of cisplatin has led to the design of many analogues to broaden the spectrum of activity, reduce side effects, and overcome resistance. Although the cis configuration was initially identified as the only active one, trans-platinum complexes have shown significant antitumour activity in preclinical models. In addition to mononuclear platinum compounds, multinuclear platinum complexes have been generated that are characterised by a different mode of interaction with DNA. Since a major limitation to the clinical efficacy of platinum compounds is drug resistance, the most important feature of nonconventional platinum drugs should be the capability of overcoming cellular resistance. However, due to the multifactorial nature of clinical resistance, which also involves pharmacological factors, the optimisation of current platinum-based therapy also includes the development of drug delivery approaches. The present review focuses on recent studies on the molecular alterations of tumour cells that are associated with resistance to platinum drugs, the development of novel platinum drugs, and approaches that may contribute to improve the efficacy of platinum-based therapy.

Shock waves (SW), defined as a sequence of single sonic pulses characterised by high peak pressure (100 MPa), a fast rise in pressure (< 10 ns) and a short lifecycle (10 μs), are conveyed by an appropriate generator to a specific target area at an energy density ranging from 0.03 to 0.11 mJ/mm2. Extracorporeal SW (ESW) therapy was first used on patients in 1980 to break up kidney stones. During the last ten years, this technique has been successfully employed in orthopaedic diseases such as pseudoarthosis, tendinitis, calcarea of the shoulder, epicondylitis, plantar fasciitis and several inflammatory tendon diseases. In particular, treatment of the tendon and muscle tissues was found to induce a long-time tissue regeneration effect in addition to having a more immediate anthalgic and anti-inflammatory outcome. In keeping with this, an increase in neoangiogenesis in the tendons of dogs was observed after 4-8 weeks of ESW treatment. Furthermore, clinical observations indicate an immediate increase in blood flow around the treated area. Nevertheless, the biochemical mechanisms underlying these effects have yet to be fully elucidated. In the present review, we briefly detail the physical properties of ESW and clinical cases treated with this therapy. We then go on to describe the possible molecular mechanism that triggers the anti-inflammatory action of ESW, focusing on the possibility that ESW may modulate endogenous nitric oxide (NO) production either under normal or inflammatory conditions. Data on the rapid enhancement of endothelial NO synthase (eNOS) activity in ESW-treated cells suggest that increased NO levels and the subsequent suppression of NF-κB activation may account, at least in part, for the clinically beneficial action on tissue inflammation.

Nitric oxide (NO) is a short-life molecule produced by the enzyme known as the nitric oxide synthase (NOS), in a reaction that converts arginine and oxygen into citrulline and NO. There are three isoforms of the enzyme: neuronal NOS (nNOS, also called NOS1), inducible NOS (iNOS or NOS2), and endothelial NOS (eNOS or NOS3). It is now known that each of these isoforms may be expressed in a variety of tissues and cell types. This paper is a review of the current knowledge of various functions of NO in diseases. We discuss in more detail its role in Cancer, the role of NO in myocardial pathophysiology, in central nervous system (CNS) pathologies. Other diseases such as inflammation, asthma, in chronic liver diseases, inflammatory bowel disease (IBD), arthritis, are also discussed. This review also covers the role of NO in cardiovascular, central nervous, pancreas, lung, gut, kidney, myoskeletal and chronic liver diseases (CLD). The ubiquitous role that the simple gas nitric oxide plays in the body, from maintaining vascular homeostasis and fighting infections to acting as a neurotransmitter and its role in cancer, has spurred a lot of interest among researchers all over the world. Nitric oxide plays an important role in the physiologic modulation of coronary artery tone and myocardial function. Nitric oxide from iNOS appears to be a key mediator of such glial-induced neuronal death. The high sensitivity of neurons to NO is partly due to NO causing inhibition of respiration, rapid glutamate release from both astrocytes and neurons, and subsequent excitotoxic death of the neurons.

Degenerative diseases are still a challenging issue in clinical therapy; even though in several cases it is possible to treat symptoms, drugs able to block disease progression are lacking at present. Osteoarthritis (OA) and Rheumatoid Arthritis (RA) are degenerative diseases leading to serious cartilage destruction, affecting joint functions and giving rise to restricted movement, pain and chronic disability. Current clinical treatment for arthritis is confined to Non Steroidal Anti- Inflammatory Drugs (NSAIDs), which are effective in treating symptoms but fail to block the progression of the disease. Matrix Metalloproteases (MMPs) inhibitors have been clinically studied as possible drugs for cartilage degradation prevention. However, their clinical use has been limited by severe side-effects. Aggrecan, which plays a fundamental role in maintaining the structural and mechanical properties of cartilage, has recently been found to be specifically cleaved by “aggrecanases”. Aggrecanases are multidomain zinc metalloproteases, different from MMPs, which cleave the aggrecan within the interglobular domain (IGD). Aggrecan breakdown at this site has been found to be crucial for cartilage degradation. These new findings re-addressed the interest of the research for new arthritis therapeutic agents focusing on aggrecanases rather than on MMPs. This review is meant to provide a critical appraisal of the ongoing developments of Znchelating and non chelating aggrecanase inhibitors, with a particular emphasis on the related structure-activity relationships (SARs), in the light of the protein structural information recently made available.

Iron chelators are being examined as a potential class of pharmaceutical agents to battle different types of cancer as well as iron overload diseases. In recent studies, iron binding species such as desferrioxamine, triapine, tachpyridine, Dp44Mt, and PIH have been tested in cell line tests and clinical trials. Using published chemical equilibrium values (stability constants, equilibrium constants), it is argued that an iron chelator cannot competitively remove iron from a heme-containing biomolecule (i.e. hemoglobin (Hb), myoglobin) causing a cancerous cell to die. This type of reaction (DFO(aq) + [Fe²⁺,³⁺-Hb] → [Fe²⁺,³⁺-DFO] + Hb) has been proposed in a number of published studies using circumstantial evidence. It is argued that iron chelators can potentially interact with iron from ferritin or iron that has precipitated or flocculated as oxyhydroxide under physiological pH's. It is argued that chelators can interfere with various physiological processes by binding cations such as Ca2+, Zn2+ or K+. A number of siderophores and natural products that have the ability to bind Fe³⁺/Fe²⁺ as well as other cations are discussed in terms of their potential pharmaceutical activity as chelators. Chemical equilibria between cations and pharmaceutical agents, which are rarely quantitated in explaining medicinal mechanisms, are used to show that chelators can bind and remove iron and other cations from physiologically important systems required for cell survival and propagation.

Substituted 2-arylbenzothiazoles have emerged in recent years as an important pharmacophore in a number of diagnostic and therapeutic settings. Attractive features of drug candidates based on this benzothiazole scaffold include their synthetic accessibility, and synthetic approaches to 2-arylbenzothiazole-based compounds will be reviewed here. Examples of 2-arylbenzothiazoles endowed with diagnostic/therapeutic activity include the 2-(4-aminophenyl)benzothiazole series, which has a remarkable activity profile in both the potential non-invasive diagnosis of Alzheimer's disease and as antitumour agents.

Dopamine and serotonin are important neurotransmitters in the mammalian central nervous system (CNS) involved in numerous physiological and behavioural disorders such as schizophrenia, major depression, anxiety, Parkinson's and Huntington's diseases, and attention deficit hyperactivity disorder. Several natural and synthetic benzylisoquinoline derivatives have displayed affinity for dopamine and serotonin receptors in nanomolar or micromolar ranges. This review covers the last three decades of dopaminergic and serotonergic activities, and especially focuses on structureactivity relationships of natural and synthetic benzylisoquinoline derivatives. We have included aporphines, 1- benzyltetrahydroisoquinolines, bis-benzylisoquinolines, protoberberines, cularines and other structural analogues. Further molecular modelling calculations have been considered as important tools to not only obtain structural information of both neurotransmitter receptors, but to also identify their pharmacophore features. The development of selective potential ligands like benzylisoquinoline derivatives may help in the therapy of diseases related to CNS dysfunction.

Fentanyl is the prototype of the 4-anilidopiperidine class of synthetic opioid analgesics. This study was aimed to review the structure-activity-relationship (SAR) of fentanyl analogs substituted in the position 3, or 4 of the piperidine ring. Pharmacological results show that the groups in position 3 of the piperidine ring, which are larger than methyl, severely reduce the analgesic potency compared to fentanyl. It is likely that the steric factor alone (i.e. voluminosity of the group and cis/trans isomerism), rather than the polarity and/or chemical reactivity, plays a crucial role in the analgesic potency of this series. Although the duration of action, in general, does not depend on the stereochemistry, longer action of the most potent 3-alkyl fentanyl analogs such as cis-3-methyl- and cis-3-ethyl fentanyl, is more likely influenced by pharmacodynamic, rather than pharmacokinetic variables. Also, it is possible that the introduction of a functional group such as 3-carbomethoxy reduces the duration of action by altering pharmacokinetic properties. SAR findings obtained by evaluating the neurotoxic effects of fentanyl analogs substituted in the position 3 of the piperidine ring parallel the SAR findings on analgesia in regard to potency and duration of action. This might suggest that similar receptors are involved in producing both antinociceptive and neurotoxic effects of these drugs. It appears that both the potency and the duration of action in the series of fentanyl analogs substituted in position 4 of the piperidine ring is influenced only by the steric requirement and not by the chemical nature of the substituent.

The dawning of this millennium broke new ground in life science and technology, presented us genomic and proteomic revolution, nanotechnology innovation, and high performance liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS) used for separating and identifying new chemical entities at pico-, or even femtoconcentrations. Applications of these high technologies to the traditional Chinese medicine (TCM) opened a new chapter in the ancient medicine, and prompted us to re-evaluate the thousand-year-old phytomedicine-ginseng from current perspectives. We, therefore, collected the latest information (mostly within 10 years) on ginseng, and condensed the information into two parts of this review serial. The present part covers etymology of ginseng, its pharmacognosy (natural origin, physical appearance, chemical properties, and specie identification), its cultivation and processing-related metabolic changes in active ingredients, standardized analytical methods used for quality control of various ginseng products, modern analytical methods used to identify and classify more than 100 chemical entities (many were recently unfolded) derived from ginseng species and their metabolites. The global markets and production of ginseng and relevant government regulations are herein updated to exchange information and understandings about current people's uses and cultivation of ginseng. The second part of the review serial will classify all these 100 chemical entities separated from various ginseng species into different groups based on their structural similarities, and summarize bioactivities of these entities. The second part of the review serial will also focus on recent findings of ginseng pharmacology and its clinical trials for various diseases, and brief side effects of ginseng.