Current Medicinal Chemistry - Volume 13, Issue 28, 2006

Gum resin extracts of Boswellia species have been traditionally applied in folk medicine forcenturies to treat various chronic inflammatory diseases, and experimental data from animal models andstudies with human subjects confirmed the potential of B. spec extracts for the treatment of not onlyinflammation but also of cancer. Analysis of the ingredients of these extracts revealed that the pentacyclictriterpenes boswellic acids (BAs) possess biological activities and appear to be responsible for the respectivepharmacological actions. Approaches in order to elucidate the molecular mechanisms underlying thebiological effects of BAs identified 5-lipoxygenase, human leukocyte elastase, toposiomerase I and II, as wellas IκB kinases as molecular targets of BAs. Moreover, it was shown that depending on the cell type and thestructure of the BAs, the compounds differentially interfere with signal transduction pathways including Ca2+-and MAPK signaling in various blood cells, related to functional cellular processes important forinflammatory reactions and tumor growth. This review summarizes the biological actions of BAs on thecellular and molecular level and attempts to put the data into perspective of the beneficial effects manifested inanimal studies and trials with human subjects related to inflammation and cancer.

Nature is an inexhaustible source of natural compounds with interesting biological activities. Ingeneral, natural products are an important source of new compounds with a variety of structural arrangementsand singular properties. Styryl lactones are a group of secondary metabolites ubiquitous in the genusGoniothalamus that have demonstrated to possess interesting biological properties, in particularantiproliferative activity against cancer cells. In general, the cytotoxicity of styryl lactones appears to bespecific against cancer cells since insignificant effects of these compounds on normal cells are reported. Alarge body of evidence suggests that the antiproliferative activity of styryl lactones is associated with theinduction of apoptosis in target cells. In the first part of this review we discuss the biological activities ofstyryl lactones focusing on cancer cells, the causal agent of Chagas' disease and the vectors for yellow feverand human lymphatic filariasis. Structure-activity relationships are described in detail for ninety styryllactones. The last part describes the molecular targets of styryl lactones for inducing apoptosis, as well asimmunosuppressive and inflammatory processes. Overall, understanding how these compounds exert theiractivities in biological system is essential for future development and application of styryl lactones forhuman health.

Primarily statin drugs inhibit hepatic 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA)reductase, which is responsible for the reduction in circulating low-density lipoprotein (LDL) cholesterol.Several findings from recent research studies indicate that statins have multiple actions that favorablyinfluence key factors involved in the atherogenic process. These so-called pleiotropic properties affect variousaspects of cell function, inflammation, coagulation, and vasomotor activity. These effects are mediated eitherindirectly through LDL cholesterol reduction or via a direct effect on cellular functions. Such actions maycontribute to the early cardiovascular benefit observed in several outcome trials with statin drugs therapy.Although many of the pleiotropic properties of statins may be a class effect, some may be unique to certainagents and account for differences in their pharmacological activity. This review summarise the results of the major outcome trials of statins and non-statins therapy and thepossible mechanisms beyond lipid lowering contributing to plaque stability.

Benign prostatic hyperplasia (BPH) is a common condition in aging men that is characterized bynonmalignant enlargement of the prostate gland, and is frequently accompanied by urinary obstruction, andlower urinary tract symptoms (LUST). Currently pharmacotherapy of BPH is based on two classes of drugs: α1-adrenoceptor (α1-AR) antagonists and α5-reductase inhibitors. It has been shown that α1-AR antagonistsreduce symptom scores and increase peak urinary flow rates in BPH. Of particular importance for BPH therapyare uroselective α1-AR antagonists for which the hypotensive related side-effect caused by α1-AR blockade isreduced. α5-Reductase inhibitors reduce prostate volume and symptom scores, while increasing peak urinaryflow rates. This review describes new α1-AR antagonists and 5α-reductase inhibitors in the treatment of BPH.The new α1-AR antagonists represent various structures such as quinazolines, phenylethylamines, piperidines,and arylpiperazines.5α-Reductase inhibitors are classified into two groups: steroidal and non-steroidal. Thenewer non-steroidal inhibitors include derivatives of benzo[c]quinolizinones, benzo[f]quinolonones,piperidones and carboxylic acids. Besides the development of new compounds belonging to the abovementioned groups, new agents for BPH treatment are sought among combined 5α-reductase/α1-AR inhibitors,endothelins, androgen receptors antagonists, growth factors, estrogens and phosphodiesterase isoenzymes aswell as several phytomedicines, used for prevention and treatment of prostate disorders. These new agents canbe used for the design of future targets and development of new drugs in the treatment of BPH. The discoveryof a number of active leads may also ultimately help in developing new safe and effective drugs.

Cholinesterase inhibitors constitute the standard of care for Alzheimer's disease in westerncountries. Donepezil, rivastigmine and galantamine had showed similar efficacy according to meta-analysisfrom randomised clinical trials. A mean modest 2 point-improvement has been observed in the Alzheimer'sdisease Assessment Scale (ADAS). Memantine has emerged as an alternative for advanced stages of the disease.Apart from clinical scales, neuroradiologic techniques have proven useful to assess the effect of these drugs onthe brain of AD patients. Methods. An extensive search for papers dealing with neuroradiological techniques in the assessment of AD drugs has been conducted, especially based on MEDLINE and EMBASE systems. Results. Several techniques have demonstrated to be useful to assess the effects of drugs and diseaseprogression. Magnetic Resonance Imaging (MRI)-based volumetry of the hippocampus showed moreconsistency to monitor progression than clinical variables, and thus, the sample size for clinical trials may bereduced. Donepezil is able to slow progression of atrophy in two controlled studies suggesting aneuroprotective effect Proton Magnetic Resonance Spectroscopy (MRS) measures metabolite concentration of living tissues. In AD the most characteristic findings are decreased N-acetyl aspartate (neuronal marker) and choline-compoundselevation (marker of cell membrane turnover and degradation). A placebo controlled trial showed thattreatment with donepezil increased transiently the NAA/Cr ratio in both hippocampi in AD. Changes inaspartate levels correlated to clinical response to rivastigmine in a non-randomised trial. Some studies evaluated cholinesterase inhibition in vivo with PET (Positron Emission Tomography) withhigher reductions for rivastigmine than for donepezil in several cortical areas. Metabolism of glucose was alsostudied in patients taking galantamine or rivastigmine. Rivastigmine may stabilise glucose metabolism in asmall series of AD patients. Correlation between glucose metabolism and changes in clinical scales has beenobserved in patients treated with galantamine. Most studies point to the frontal cortex as the best area to detectchanges after treatment with cholinesterase inhibitors. Conclusions. Neuroradiologic techniques are of help to evaluate the effect of drugs in AD, and to monitordisease progression.

Currently available therapies for brain ischemia, with a few exceptions, provide only symptomaticrelief in patients. Recent investigations in experimental models provided an understanding of the cellular andmolecular mechanisms that lead to neurodegeneration in ischemic injury, and also indicate targets forprevention and amelioration of the devastating consequences of stroke. An enormous increase in intracellularfree Ca2+ levels following stroke activates Ca2+-dependent enzymes, contributing to neuronal death anddysfunction. Additionally, ischemic injury generates highly reactive free radicals and triggers release ofcytotoxic cytokines for activation of cysteine proteases. A number of studies already indicated a prominentrole for the cysteine proteases of the calpain and caspase families in the pathogenesis of brain ischemia.Proteolytic activities of these proteases degrade various cytoskeletal proteins and membrane proteins,destabilizing the structural integrity and forcing the neurons to delayed death in ischemic penumbra. Somecurrent studies have unequivocally confirmed the neuronal apoptosis in ischemia and showed thatadministration of calpain and caspase inhibitors alone or in combination can provide functionalneuroprotection in various animal models of cerebral ischemia. This article will discuss the molecularstructures and activities of calpain and caspase inhibitors and their therapeutic efficacy in experimental brainischemia. However, further investigations are necessary for improvements in the structural design of calpainand caspase inhibitors for their persistent therapeutic efficacy in animal models of stroke and for clinical trialsin the future.

The main threshold for the therapeutic applications of nucleotides and oligonucleotides is theirionic structure which implies poor cellular uptake and unfavorable pharmacokinetic parameters. To circumventthese problems, the anionic phosphate moieties may be temporarily masked with enzymolabile protectinggroups to form neutral pronucleotides or pro-oligonucleotides. In cells, enzymes cleave the protecting groupsand release the parent drug. Several prodrug strategies have been developed, but the kinetics and mechanismsof the deprotection of potential prodrug candidates are still often poorly known. The purpose of the presentreview is to summarize the current knowledge on the chemical aspects of alternative prodrug strategies atnucleotide and oligonucleotide level.

Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting witha family of adenosine receptors known as A1, A2A, A2B, and A3. The A2B subtype is a low affinity receptor,which couples to stimulation of adenylyl cyclase and also leads to a rise in intracellular calcium modulatingimportant physiological processes. Adenosine exhibiting activity at this subtype is at concentrations greaterthan 10 μM. The A2B receptors show a ubiquitous distributions, the highest levels are present in cecum, colonand bladder, followed by blood vessels, mast cells and lung. Through A2B receptors, adenosine also regulatesthe growth of smooth muscle cell populations in blood vessels, cell growth, intestinal function, inhibition ofTumor Necrosis Factor (TNF-α), vascular tone, and inflammatory processes such as diarrhea and asthma. Potent and selective adenosine agonists are the result of modifications of the parent ligand adenosine bysubstitution, namely at N6 or C2 position of the purine heterocycle or at the 5' position of the ribose moiety.5'-N-ethylcarboxamidoadenosina (NECA) is one of the most potent A2B adenosine receptor agonist. Classicalantagonists for A2B adenosine receptors are xanthine analogues obtained from multiple substitutions of theparent heterocycle by C8 substitution combined with N1 and N3 (and sometimes N7) substitutions.