Current Medicinal Chemistry - Volume 13, Issue 9, 2006

Despite the technical progress in interventional techniques to overcome the harmful effects of ischemic heart disease there is still an urgent need for alternative, pharmaceutical treatment modalities. Exogenous stimulation of vessel growth, i.e. vasculogenesis, angiogenesis or arteriogenesis serves as a promising strategy to restore blood flow to the jeopardized tissue regions downstream of arterial stenosis or occlusion. While vasculogenesis is defined as the arrangement of angioblasts during prenatal development creating the first vascular network, angiogenesis and arteriogenesis refer to important adaptive mechanisms in the adult organism. Angiogenesis, neo-formation of capillaries, is a key process in many different physiological and pathophysiological events where improvement of microvascular function and tissue nutrition is needed (e.g. wound healing, tumor growth). In contrast to this capillary sprouting, the term arteriogenesis refers to the development of large caliber collateral arteries. Under conditions of increasing shear stress, anastomoses between interconnected perfusion territories can undergo adaptive enlargement, developing into a functional network of collateral arteries, natural bypasses able to maintain sufficient blood flow and compensating for the gradual occlusion of a large artery (e.g. in the coronary circulation). However, in most cases arteriogenesis does not proceed as fast as the stenosis progresses and infarction and tissue necrosis results. A well-developed collateral network is an important protective factor for the occurrence of ischemic events and therefore pharmaceutical acceleration and stimulation of arteriogenesis in patients represents an eminent aim for the future. This review focuses on the basic mechanisms of arteriogenesis, the recent progresses in translating these insights into the clinical situation and the problems yet to be solved.

Epidemiological studies demonstrated that even in the absence of other risk factors (e.g. diabetes, hypertension, hyperhomocysteinemia, hypercholesterolemia), advanced age itself significantly increases cardiovascular morbidity by enhancing vascular oxidative stress and inflammation. Because the population in the Western world is rapidly aging, there is a substantial need for pharmacological interventions that delay the functional decline of the cardiovascular system. Resveratrol is an atoxic phytoestrogen found in more than 70 plants including grapevine and berries. Recent data suggest that nutritional intake of resveratrol and other polyphenol compounds may contribute to the "French paradox", the unexpectedly low cardiovascular morbidity in the Mediterranean population. There is increasing evidence that resveratrol exerts multifaceted anti-oxidant and/or anti-inflammatory effects in various disease models. Importantly, resveratrol was reported to slow aging and increase lifespan in simple organisms and has been suggested as a potential calorie restriction mimetic. Resveratrol has also been reported to activate NAD-dependent histone deacetylases (sirtuins), which may contribute to its anti-aging effects. This review focuses on the role of oxidative stress and inflammation in cardiovascular dysfunction in aging, and on emerging anti-aging therapeutic strategies offered by resveratrol and other polyphenol compounds.

The enterohepatic circulation of bile acids is a major regulator of serum cholesterol homeostasis. After biosynthesis from cholesterol in the liver, bile acids are secreted with bile into the lumen of the small intestine to aid in the digestion and absorption of fat and fat-soluble vitamins. The bile acids are nearly quantitatively reabsorbed in the terminal ileum by a Na+-dependent transport system (IBAT) and are transported with portal blood to the liver and taken up by a second Na+-/bile acid cotransporter (LBAT) to be resecreted into bile. In the liver bile acids inhibit the rate-limiting enzyme for the conversion of cholesterol into bile acid: cholesterol-7α-hydroxylase; interruption of the enterohepatic circulation of bile acids withdraws this feedback inhibition and leads to an upregulation of hepatic LDL-receptors with a concomitant decrease of serum LDL-levels. Specific inhibitors of the ileal bile acid transporter belonging to different chemotypes have been developed in recent years for this purpose, some now entering clinical stage. To exert a profound systemic effect these compounds do not need to be available systemically but can act from the luminal side of the small intestine, which offers the advantage to avoid the well-known adverse side effects of other hypolipidemic drugs like statins due to metabolism and drug-drug interactions in the liver. This implies several aspects in compound optimization and drug development quite different from standard procedures, for example the concept of low absorption drugs was established to avoid systemic side effects. The review article covers the mechanistic and therapeutic principles of the approach and presents an overview on the molecular target, the discovery of specific inhibitors and respective optimization strategies.

The ionotropic glutamate receptor NMDA is allosterically modulated by glycine, a coagonist, its presence is an absolute requirement for receptor activation. The transport of glycine in glutamatergic synapse is carried out by glycine transporter-1 (GlyT1), a Na+/Cl--dependent carrier molecule. The primary role of GlyT1 is to maintain glycine concentrations below saturation level at postsynaptic NMDA receptors. Several isoforms of GlyT1 (a-e) have been identified, which are expressed both in glial and neuronal cell membranes. GlyT1 operates bidirectionally: it decreases synaptic glycine concentration when operates in normal mode and releases glycine from glial cells as operates in a reverse mode. It is expected that non-transportable, non-competitive inhibitors of GlyT1 may have therapeutic value in CNS disorders characterized by hypofunctional NMDA receptor-mediated glutamatergic neurotransmission. Accordingly, GlyT1 inhibitors exhibited antipsychotic profile in a number of animal tests. The first promising in vitro and in vivo experiments with glycine itself, and its N-methyl analogue, sarcosine, had initiated the syntheses of potential GlyT1 inhibitors with more complex structures, in which, however, the glycine or sarcosine moiety had always been incorporated. Those attempts led to the development of two compounds, ALX-5407 and Org-24461 with high inhibitory potency; however, none of which is now considered as a drug candidate due, most probably, to safety and/or pharmacokinetic issues. More recently, several structurally new series of highly potent inhibitors with no aminomethylcarboxy group have also been discovered. Some of them might be expected to fulfill all requirements for clinical development. The new generation of GlyT1 inhibitors may represent a novel treatment of patients suffering from schizophrenia and/or other neuropathological conditions.

Carboxylesterases (CE) are ubiquitous enzymes responsible for the detoxification of xenobiotics. Many therapeutically useful drugs are metabolized by these proteins which impacts upon the efficiency of drug treatment. In some instances, CEs convert inactive prodrugs to active metabolites, a process that is essential for biological activity. Such compounds include the anticancer agents CPT-11 (3) and capecitabine (4), the antibiotics Ceftin (9) and Vantin, as well as the illicit street drug heroin (6). However, more commonly, CEs hydrolyze many esterified drugs to inactive products that are then excreted. Agents such as flestolol (11), meperidine (5), lidocaine (8) and cocaine (7), are all hydrolyzed and inactivated by these enzymes. Therefore the efficacy of esterified drugs will be dependent upon the distribution and catalytic activity of different CEs. In this review, we examine the structural aspects of CEs and their roles in drug detoxification and propose that modulation of CE activity may allow for improvements in, and potentiation of, drug efficacy.

Silymarin is a purified extract from milk thistle (Silybum marianun (L.) Gaertn), composed of a mixture of four isomeric flavonolignans: silibinin (its main, active component), isosilibinin, silydianin and silychristin. This extract has been empirically used as a remedy for almost 2000 years, and remains being used as a medicine for many types of acute and chronic liver diseases. Despite its routinely clinical use as hepatoprotectant, the mechanisms underlying its beneficial effects remain largely unknown. This review addresses in detail a number of recent studies showing a novel feature of silymarin as a hepatoprotective drug, namely: its anticholestatic properties in experimental models of hepatocellular cholestasis with clinical correlate. For this purpose, this review will cover the following aspects: 1. The chemistry of silymarin, including chemical composition and properties. 2. The current clinical applications of silymarin as a hepatoprotective agent, including the mechanisms by which silymarin is thought to exert its hepatoprotective properties, when known. 3. The physiological events involved in bile formation, and the mechanisms of hepatocellular cholestasis, focusing on cellular targets and mechanisms of action of drugs used to reproduce experimentally cholestatic diseases of clinical interest, in particular estrogens and monohydroxylated bile salts, where anticholestatic properties of silymarin have been tested so far. 4. The recent findings describing the impact of silymarin on normal bile secretion and its novel, anticholestatic properties in experimental models of cholestasis, with particular emphasis on the cellular/molecular mechanisms involved, including modulation of bile salt synthesis, biotransformation/depuration of cholestatic compounds, changes in transporter expression/activity, and evocation of signaling pathways.

Increasing evidence demonstrates that oxidative stress causes damage to cell function with aging and is involved in a number of age-related disorders including atherosclerosis, arthritis, and neurodegenerative disorders. Cellular changes show that oxidative stress is a condition that precedes the appearance of the hallmark pathologies of the disease, neurofibrillary tangles and senile plaques. The aim of this article is to analyze the different biomarkers of oxidative stress in Alzheimer patients, in different stages of the illness, and compare the results with a control group. A nutritional evaluation was carried out, including anthropometric and biological measures and a 3 day dietary record. The concentration of substances which react to thiobarbituric acid (TBARS) was measured as a marker of the degree of peroxidation using the HPLC method. The oxidation of proteins was analyzed by measuring the carbonyl groups in plasma. In addition, measurements were made of the total antioxidant activity in plasma and the activity of endogenous antioxidant enzymes such as gluthatione peroxidase, gluthatione reductase and superoxide dismutase. The total antioxidant plasmatic status of the patients with Alzheimer both in light-moderate phase and in advanced phase was lower than in the control. No significant differences were observed between the different stages of the disease in protein oxidation levels. Peroxidation was higher in patients in the advanced stage of the disease than in the control group. However, no significant differences were observed between the different stages of the disease. In this preliminary study, it was observed that Alzheimer patients in the light-moderate stage already present oxidative stress levels above those of the control group.

Cancer is one of the major cases of death in the world. Current treatment of cancer is limited to surgery, radiotherapy, and the use of cytotoxic agents, despite their well known side effects and problems associated with the development of resistance. For most forms of disseminated cancer, however, no curative therapy is available, and the discovery and development of novel active chemotherapeutic agents is largely needed. Since the development of cisplatin, an inorganic platinum complex, numerous platinum and non-platinum metal complexes were synthesized and tested for anticancer activity. Very few match the clinical efficacy of cisplatin. Ruthenium complexes were prepared to ameliorate cisplatin activity, particularly on resistant tumours, or to reduce host toxicity at active doses. Since many years a lot of scientific groups have actively worked in the field of inorganic antitumor drugs and have developed a number of Ru(II) and Ru(III) complexes, which were shown to possess good antitumor and, above all, antimetastatic properties against animal models. Ruthenium complexes are presently an object of great attention in the field of medicinal chemistry, as antitumor agents with selective antimetastatic properties and low systemic toxicity. Ruthenium compounds appear to penetrate reasonably well the tumor cells and bind effectively to DNA. In this review, the achievements in the field of medicinal chemistry, DNA binding modes, and the development status of Ru(II) and Ru(III) complexes as anticancer agents are discussed. The aim of this review is therefore that of critically examining the past and the actual work on ruthenium compounds with emphasis on their proposed role in cancer therapy.