Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 13, Number 28, 2006

Contents


Boswellic Acids: Biological Actions and Molecular Targets Pp. 3359-3369
Daniel Poeckel and Oliver Werz
[Abstract]


Styryl Lactones and Their Derivatives: Biological Activities, Mechanisms of Action and Potential Leads for Drug Design Pp. 3371-3384
Â. de Fátima, L.V. Modolo, L.S. Conegero, R.A. Pilli, C.V. Ferreira, L.K. Kohn and J.E. de Carvalho
[Abstract]


Statin Therapy-Evidence Beyond Lipid Lowering Contributing to Plaque Stability Pp. 3385-3393
Ferruccio de Lorenzo, Michael Feher, Juliette Martin, Sophie Collot-Teixeira, Olena Dotsenko and John Louis McGregor
[Abstract]


Trends in the Development of New Drugs for Treatment of Benign Prostatic Hyperplasia Pp. 3395-3416
Katarzyna Kulig and Barbara Malawska
[Abstract]


The Effect of Drugs for Alzheimer Disease Assessed by Means of Neuroradiological Techniques Pp 3417-3224
Pedro J. Modrego
[Abstract]


Currently Evaluated Calpain and Caspase Inhibitors for Neuroprotection in Experimental Brain Ischemia Pp. 3425-3440
Swapan K. Ray
[Abstract]


Prodrug Approaches of Nucleotides and Oligonucleotides Pp. 3441-3465
Päivi Poijärvi-Virta and Harri Lönnberg
[Abstract]


Ligands for A_2B Adenosine Receptor Subtype Pp. 3467-3482
Pier Giovanni Baraldi, Romeo Romagnoli, Delia Preti, Francesca Fruttarolo, Maria Dora Carrion and Mojgan Aghazadeh Tabrizi
[Abstract]




Abstracts


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Boswellic Acids: Biological Actions and Molecular Targets
Daniel Poeckel and Oliver Werz

Gum resin extracts of Boswellia species have been traditionally applied in folk medicine for centuries to treat various chronic inflammatory diseases, and experimental data from animal models and studies with human subjects confirmed the potential of B. spec extracts for the treatment of not only inflammation but also of cancer. Analysis of the ingredients of these extracts revealed that the pentacyclic triterpenes boswellic acids (BAs) possess biological activities and appear to be responsible for the respective pharmacological actions. Approaches in order to elucidate the molecular mechanisms underlying the biological effects of BAs identified 5-lipoxygenase, human leukocyte elastase, toposiomerase I and II, as well as IκB kinases as molecular targets of BAs. Moreover, it was shown that depending on the cell type and the structure 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 for inflammatory reactions and tumor growth. This review summarizes the biological actions of BAs on the cellular and molecular level and attempts to put the data into perspective of the beneficial effects manifested in animal studies and trials with human subjects related to inflammation and cancer.


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Styryl Lactones and Their Derivatives: Biological Activities, Mechanisms of Action and Potential Leads for Drug Design
Â. de Fátima, L.V. Modolo, L.S. Conegero, R.A. Pilli, C.V. Ferreira, L.K. Kohn and J.E. de Carvalho

Nature is an inexhaustible source of natural compounds with interesting biological activities. In general, natural products are an important source of new compounds with a variety of structural arrangements and singular properties. Styryl lactones are a group of secondary metabolites ubiquitous in the genus Goniothalamus that have demonstrated to possess interesting biological properties, in particular antiproliferative activity against cancer cells. In general, the cytotoxicity of styryl lactones appears to be specific against cancer cells since insignificant effects of these compounds on normal cells are reported. A large body of evidence suggests that the antiproliferative activity of styryl lactones is associated with the induction of apoptosis in target cells. In the first part of this review we discuss the biological activities of styryl lactones focusing on cancer cells, the causal agent of Chagas’ disease and the vectors for yellow fever and human lymphatic filariasis. Structure-activity relationships are described in detail for ninety styryl lactones. The last part describes the molecular targets of styryl lactones for inducing apoptosis, as well as immunosuppressive and inflammatory processes. Overall, understanding how these compounds exert their activities in biological system is essential for future development and application of styryl lactones for human health.


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Statin Therapy-Evidence Beyond Lipid Lowering Contributing to Plaque Stability
Ferruccio de Lorenzo, Michael Feher, Juliette Martin, Sophie Collot-Teixeira, Olena Dotsenko and John Louis McGregor

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 favorably influence key factors involved in the atherogenic process. These so-called pleiotropic properties affect various aspects of cell function, inflammation, coagulation, and vasomotor activity. These effects are mediated either indirectly through LDL cholesterol reduction or via a direct effect on cellular functions. Such actions may contribute 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 certain agents 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 the possible mechanisms beyond lipid lowering contributing to plaque stability.


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Trends in the Development of New Drugs for Treatment of Benign Prostatic Hyperplasia
Katarzyna Kulig and Barbara Malawska

Benign prostatic hyperplasia (BPH) is a common condition in aging men that is characterized by nonmalignant enlargement of the prostate gland, and is frequently accompanied by urinary obstruction, and lower urinary tract symptoms (LUST). Currently pharmacotherapy of BPH is based on two classes of drugs:α₁ -adrenoceptor (α₁-AR) antagonists and 5α-reductase inhibitors. It has been shown that α₁-AR antagonists reduce symptom scores and increase peak urinary flow rates in BPH. Of particular importance for BPH therapy are uroselective α₁-AR antagonists for which the hypotensive related side-effect caused by α₁-AR blockade is reduced. 5α-Reductase inhibitors reduce prostate volume and symptom scores, while increasing peak urinary flow 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. The newer 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 above mentioned 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 as well as several phytomedicines, used for prevention and treatment of prostate disorders. These new agents can be used for the design of future targets and development of new drugs in the treatment of BPH. The discovery of a number of active leads may also ultimately help in developing new safe and effective drugs.


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The Effect of Drugs for Alzheimer Disease Assessed by Means of Neuroradiological Techniques
Pedro J. Modrego

Cholinesterase inhibitors constitute the standard of care for Alzheimer’s disease in western countries. Donepezil, rivastigmine and galantamine had showed similar efficacy according to meta-analysis from randomised clinical trials. A mean modest 2 point-improvement has been observed in the Alzheimer’s disease 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 on the 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 disease progression. Magnetic Resonance Imaging (MRI)-based volumetry of the hippocampus showed more consistency to monitor progression than clinical variables, and thus, the sample size for clinical trials may be reduced. Donepezil is able to slow progression of atrophy in two controlled studies suggesting a neuroprotective 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-compounds elevation (marker of cell membrane turnover and degradation). A placebo controlled trial showed that treatment with donepezil increased transiently the NAA/Cr ratio in both hippocampi in AD. Changes in aspartate levels correlated to clinical response to rivastigmine in a non-randomised trial.

Some studies evaluated cholinesterase inhibition in vivo with PET (Positron Emission Tomography) with higher reductions for rivastigmine than for donepezil in several cortical areas. Metabolism of glucose was also studied in patients taking galantamine or rivastigmine. Rivastigmine may stabilise glucose metabolism in a small series of AD patients. Correlation between glucose metabolism and changes in clinical scales has been observed in patients treated with galantamine. Most studies point to the frontal cortex as the best area to detect changes after treatment with cholinesterase inhibitors.

Conclusions. Neuroradiologic techniques are of help to evaluate the effect of drugs in AD, and to monitor disease progression.


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Currently Evaluated Calpain and Caspase Inhibitors for Neuroprotection in Experimental Brain Ischemia
Swapan K. Ray

Currently available therapies for brain ischemia, with a few exceptions, provide only symptomatic relief in patients. Recent investigations in experimental models provided an understanding of the cellular and molecular mechanisms that lead to neurodegeneration in ischemic injury, and also indicate targets for prevention and amelioration of the devastating consequences of stroke. An enormous increase in intracellular free Ca²⁺ levels following stroke activates Ca²⁺-dependent enzymes, contributing to neuronal death and dysfunction. Additionally, ischemic injury generates highly reactive free radicals and triggers release of cytotoxic cytokines for activation of cysteine proteases. A number of studies already indicated a prominent role 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. Some current studies have unequivocally confirmed the neuronal apoptosis in ischemia and showed that administration of calpain and caspase inhibitors alone or in combination can provide functional neuroprotection in various animal models of cerebral ischemia. This article will discuss the molecular structures and activities of calpain and caspase inhibitors and their therapeutic efficacy in experimental brain ischemia. However, further investigations are necessary for improvements in the structural design of calpain and caspase inhibitors for their persistent therapeutic efficacy in animal models of stroke and for clinical trials in the future.


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Prodrug Approaches of Nucleotides and Oligonucleotides
Päivi Poijärvi-Virta and Harri Lönnberg

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


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Ligands for A_2B Adenosine Receptor Subtype
Pier Giovanni Baraldi, Romeo Romagnoli, Delia Preti, Francesca Fruttarolo, Maria Dora Carrion and Mojgan Aghazadeh Tabrizi

Adenosine is a naturally occurring nucleoside, which exerts its biological effects by interacting with a family of adenosine receptors known as A₁, A_2A, A_2B, and A₃. The A_2B subtype is a low affinity receptor, which couples to stimulation of adenylyl cyclase and also leads to a rise in intracellular calcium modulating important physiological processes. Adenosine exhibiting activity at this subtype is at concentrations greater than 10 μM. The A_2B receptors show a ubiquitous distributions, the highest levels are present in cecum, colon and bladder, followed by blood vessels, mast cells and lung. Through A_2B receptors, adenosine also regulates the growth of smooth muscle cell populations in blood vessels, cell growth, intestinal function, inhibition of Tumor 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 by substitution, 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 A_2B adenosine receptor agonist. Classical antagonists for A_2B adenosine receptors are xanthine analogues obtained from multiple substitutions of the parent heterocycle by C⁸ substitution combined with N¹ and N³ (and sometimes N⁷) substitutions.