Current Medicinal Chemistry
Volume 18, Number 8, 2011
Contents
▶ Resveratrol, a Phytochemical Inducer of Multiple Cell Death Pathways: Apoptosis, Autophagy and Mitotic Catastrophe Pp. 1100-1121
D. Delmas, E. Solary and N. Latruffe [Abstract]
▶ In Silico Methods to Assist Drug Developers in Acetylcholinesterase Inhibitor Design Pp. 1122-1136 J.A. Bermúdez-Lugo, M.C. Rosales-Hernández, O. Deeb, J. Trujillo-Ferrara and J. Correa-Basurto [Abstract]
▶ Phenolic Compounds from Plants as Nitric Oxide Production Inhibitors Pp. 1137-1145 F. Conforti and F. Menichini [Abstract]
▶ Lycopene and Cardiovascular Diseases: An Update Pp. 1146-1163
A. Mordente, B. Guantario, E. Meucci, A. Silvestrini, E. Lombardi, G.E. Martorana, B. Giardina and V. Böhm [Abstract]
▶ Novel Trends in the Treatment of Cardiovascular Disorders: Site- and Event-Selective Adenosinergic Drugs Pp. 1164-1187 A.J. Szentmiklósi, Á. Cseppento, G. Harmati and P.P. Nánási [Abstract]
▶ Structure-Based Approach for the Discovery of Novel Selective Estrogen Receptor Modulators Pp. 1188-1194 C. Rosano, E. Stec-Martyna, R. Lappano and M. Maggiolini [Abstract]
▶ Neuroprotective Actions of Flavonoids Pp. 1195-1212 C. Gutierrez-Merino, C. Lopez-Sanchez, R. Lagoa, A.K. Samhan-Arias, C. Bueno and V. Garcia-Martinez
[Abstract]
▶ Is Androstadienone a Putative Human Pheromone? Pp. 1213-1219
D. Marazziti, P. Torri, S. Baroni, M. Catena Dell’Osso, G. Consoli and V. Boncinelli
[Abstract]
▶ Lactoferrin: A Biologically Active Molecule for Bone Regeneration Pp. 1220-1229
A.A. Amini and L.S. Nair [Abstract]
▶ Adalimumab in Crohn’s Disease: Tips and Tricks After 5 Years of Clinical Experience Pp. 1230-1238 G. Fiorino, H. Szabò, W. Fries, A. Malesci, L. Peyrin-Biroulet and S. Danese [Abstract]
▶ Promising Targets for Anti-Hepatitis C Virus Agents Pp. 1239-1244, T. Yoshida, M. Kondoh and K. Yagi [Abstract]
▶ Chemopreventive Properties and Molecular Mechanisms of the Bioactive Compounds in Hibiscus Sabdariffa Linne Pp. 1245-1254 Hui-Hsuan Lin, Jing-Hsien Chen and Chau-Jong Wang [Abstract]
Abstracts
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Resveratrol, a Phytochemical Inducer of Multiple Cell Death Pathways: Apoptosis, Autophagy and Mitotic Catastrophe
D. Delmas, E. Solary and N. Latruffe
Cancers are the largest cause of mortality and morbidity in industrialized countries. In the field of the medicinal chemistry of natural products, numerous studies have reported interesting properties of trans-resveratrol as a chemopreventing agent against cancers, inflammation, and viral infection. Tumor growth inhibition has been linked to the ability of resveratrol to arrest cell cycle progression and to trigger cell death. This review focuses on the pathways that mediate resveratrol-induced cell death. Resveratrol impacts on the mitochondrial functions (respiratory chain, oncoproteins, gene expression, etc), in which p53 protein can be involved and its acetylated or phosphorylated forms. This polyphenol also affects death receptor distribution in ceramide-enriched membrane platforms which serve to trap and cluster receptor molecules, and facilitates the formation of a death-inducing signaling complex in the cell. To induce apoptosis, resveratrol also activates the ceramide / sphingomyelin pathway, which promotes ceramide generation and the downstream activation of kinase cascades. Resveratrol can activate alternative pathways to cell death such as those leading to autophagy, senescence or mitotic catastrophe. Furthermore, numerous attempts have been made using resveratrol analogs to improve the molecule’s ability to block cell proliferation and induce cell death. Moreover, structural modification of natural phenolics is expected to produce analogs that may be useful tools to study the structure-activity relationships. Lastly, in various cancer types, resveratrol behaves as a chemosensitizer that lowers the threshold of cell death induction by classical anticancer agents and counteracts tumor cell chemoresistance.
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In Silico Methods to Assist Drug Developers in Acetylcholinesterase Inhibitor Design
J.A. Bermúdez-Lugo, M.C. Rosales-Hernández, O. Deeb, J. Trujillo-Ferrara and J. Correa-Basurto
Alzheimer's disease (AD) is a neurodegenerative disease characterized by a low acetylcholine (ACh) concentration in the hippocampus and cortex. ACh is a neurotransmitter hydrolyzed by acetylcholinesterase (AChE). Therefore, it is not surprising that AChE inhibitors (AChEIs) have shown better results in the treatment of AD than any other strategy. To improve the effects of AD, many researchers have focused on designing and testing new AChEIs. One of the principal strategies has been the use of computational methods (structural bioinformatics or in silico methods).
In this review, we summarize the in silico methods used to enhance the understanding of AChE, particularly at the binding site, to design new AChEIs. Several computational methods have been used, such as docking approaches, molecular dynamics studies, quantum mechanical studies, electronic properties, hindrance effects, partition coefficients (Log P) and molecular electrostatic potentials surfaces, among other physicochemical methods that exhibit quantitative structure-activity relationships.
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Phenolic Compounds from Plants as Nitric Oxide Production Inhibitors
F. Conforti and F. Menichini
Nitric oxide (NO) is a diatomic free radical produced from L-arginine by constitutive and inducible nitric oxide synthase (cNOS and iNOS) in numerous mammalian cells and tissues. Nitric oxide (NO), superoxide (O2-) and their reaction product peroxynitrite (ONOO-) may be generated in excess during the host response against viral and antibacterial infections and contribute to some pathogenesis by promoting oxidative stress, tissue injury and, even, cancer. Oxidative damage, caused by action of free radicals, may initiate and promote the progression of a number of chronic diseases, including cancer, cardiovascular diseases, Alzheimer’s disease, diabetes and inflammation. The mechanism of inflammation injury is attributed, in part, to release of reactive oxygen species from activated neutrophils and macrophages. ROS propagate inflammation by stimulating release of mediators such as NO and cytokines. The interest of the research is motivated by the current need to find new substances of natural origin which have demonstrated effectiveness in the described fields of application and low degree of toxicity for humans. Natural products provide a vast pool of NO inhibitors that can possibly be developed into clinical products. This article reviews some plenolic secondary metabolites from plants with NO inhibitory properties and their structure-activity relationship studies that can be focused for drug development programs.
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Lycopene and Cardiovascular Diseases: An Update
A. Mordente, B. Guantario, E. Meucci, A. Silvestrini, E. Lombardi, G.E. Martorana, B. Giardina and V. Böhm
Cardiovascular disease (CVD) is the leading cause of death in Western societies and accounts for up to a third of all deaths worldwide. In comparison to the Northern European or other Western countries, the Mediterranean area has lower rates of mortality from cardiovascular diseases and cancer, and this is attributed, at least in part, to the so-called Mediterranean diet, which is rich in plant-derived bioactive phytochemicals. Identification of the active constituents of the Mediterranean diet is therefore crucial to the formulation of appropriate dietary guidelines.
Lycopene is a natural carotenoid found in tomato, an essential component of the Mediterranean diet, which, although belonging to the carotenoid family, does not have pro-vitamin A activity but many other biochemical functions as an antioxidant scavenger, hypolipaemic agent, inhibitor of pro-inflammatory and pro-thrombotic factors, thus potentially of benefit in CVD.
In particular, the review intends to conduct a systematic analysis of the literature (epidemiological studies and interventional trials) in order to critically evaluate the association between lycopene (or tomato products) supplementation and cardiovascular diseases and/or cardiovascular disease risk factors progression, and to prepare provision of evidence-based guidelines for patients and clinicians. Several reports have appeared in support of the role of lycopene in the prevention of CVD, mostly based on epidemiological studies showing a dose-response relationship between lycopene and CVD. A less clear and more complex picture emerges from the interventional trials, where several works have reported conflicting results. Although many aspects of lycopene in vivo metabolism, functions and clinical indications remain to be clarified, supplementation of low doses of lycopene has been already suggested as a preventive measure for contrasting and ameliorating many aspects of CVD.
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Novel Trends in the Treatment of Cardiovascular Disorders: Site- and Event-Selective Adenosinergic Drugs
A.J. Szentmiklósi, Á. Cseppento, G. Harmati and P.P. Nánási
This review focuses on the potential role of site- and event-selective adenosinergic drugs in the treatment of cardiovascular diseases. Adenosine is released from the myocardium and vessels in response to various forms of stress and acts on four receptor subtypes (A1, A2A, A2B and A3). Adenosine is an important endogenous substance with important homeostatic activity in the regulation of cardiac function and circulation. Adenosine receptors are also involved in the modulation of various cellular events playing crucial role in physiological and pathological processes of the cardiovascular system. These actions are associated to activation of distinct adenosine receptor subtypes, therefore drugs targeting specific adenosine receptors might be promising therapeutic tools in treatment of several disorders including various forms of cardiac arrhythmia, myocardial ischemia-reperfusion injury, angina pectoris, chronic heart failure, etc. Recently, in addition to subtype-specific adenosine receptor agonists and antagonists, a number of substances that enhance adenosine receptor activation locally at the site where the release of endogenous adenosine is the most intensive have been developed. Thus global actions of adenosine receptor agonists and antagonists, as well as desensitization or down-regulation following chronic administration of these orthosteric compounds can possibly be avoided. We discuss the chemical, pharmacological and clinical features of these compounds: (1) inhibitors of membrane adenosine transporters (NBTI, dipyridamole), (2) inhibitors of adenosine deaminase (coformycin, EHNA), (3) inhibitors of adenosine kinase (tubercidin, aristeromycin), (4) inhibitors of AMP deaminase (GP3269), (5) activators of 5’-nucleotidase (methotrexate), (6) adenosine regulators (acadesine) and (7) allosteric adenosine receptor modulators (PD81723, LUF6000). The development of this type of substances might offer a novel therapeutic approach for treating cardiovascular diseases in the near future.
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Structure-Based Approach for the Discovery of Novel Selective Estrogen Receptor Modulators
C. Rosano, E. Stec-Martyna, R. Lappano and M. Maggiolini
In the last twenty years the efforts to design and optimize new drugs have been based on the three dimensional structure of the selected target proteins. In this regard, useful information has been achieved mainly by protein crystallography, which has recently turned from a low into a high-throughput process thanks to the improvement in robot technologies, automation procedure and the use of synchrotron radiation facilities [1-3]. This review examines the impact of Structure Based Drug Design (SBDD) on the discovery of ligands as the selective estrogen receptor modulators (SERMs) of the Estrogen Receptor (ER)a, which is involved in the regulation of several physiological and pathological processes.
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Neuroprotective Actions of Flavonoids
C. Gutierrez-Merino, C. Lopez-Sanchez, R. Lagoa, A.K. Samhan-Arias, C. Bueno and V. Garcia-Martinez
The experimental evidences accumulated during last years point out a relevant role of oxidative stress in neurodegeneration. As anti-cellular oxidative stress agents flavonoids can act either as direct chemical antioxidants, the classic view of flavonoids as antioxidants, or as modulators of enzymes and metabolic and signaling pathways leading to an overshot of reactive oxygen species (ROS) formation, a more recently emerging concept. Flavonoids, a large family of natural antioxidants, undergo a significant hepatic metabolism leading to flavonoid-derived metabolites that are also bioactive as antioxidant agents. The development of more efficient flavonoid’s based anti-oxidative stress therapies should also take into account their bioavailability in the brain using alternate administration protocols, and also that the major ROS triggering the cellular oxidative stress are not the same for all neurodegenerative insults and diseases. On these grounds, we have reviewed the reports on neuroprotection by different classes of flavonoids on cellular cultures and model animals. In addition, as they are now becoming valuable pharmacological drugs, due to their low toxicity, the reported adverse effects of flavonoids in model experimental animals and humans are briefly discussed.
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Is Androstadienone a Putative Human Pheromone?
D. Marazziti, P. Torri, S. Baroni, M. Catena Dell’Osso, G. Consoli and V. Boncinelli
On the basis of different evidences, androstadienone, a steroid compound produced in the armpit, has been proposed as a human pheromone, although its physiological levels appear too low to induce a response under experimental conditions. For this reason, the majority of researchers in this area puts into question the “legitimacy” of androstadienone, and prefers to consider the axillary extracts in its entirety, like a sort of “medicinal tea”, the components of which still remain to be identified, but that taken together may induce a response, or function as a carrier of other active substances. Another option is that androstadienone acts with varying degrees of potency and, at lower concentrations, according to the context and to specific behavioral situations.
The aim of this paper is to review all relevant data regarding androstadienone, in order to ascertain whether it may be considered a physiological pheromone and, as such, a possible target of future modulators of some human behaviors.
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Lactoferrin: A Biologically Active Molecule for Bone Regeneration
A.A. Amini and L.S. Nair
Lactoferrin, a member of the “Siderophilin” family, is an iron binding glycoprotein. Lactoferrin is produced by various exocrine glands in our body and is abundantly present in milk and colostrums. The uniqueness of lactoferrin as a skeletal regenerative molecule lies in its ability to favorably modulate the responses of the various cell types involved in musculoskeletal regeneration. Lactoferrin exhibits pleiotropic functions and recent studies indicate that lactoferrin promotes the proliferation and differentiation of osteoblast cells and inhibits osteoclast-mediated bone resorption. Human lactoferrin is also known to promote neovascularization. This review aims to summarize the most recent studies on lactoferrin focusing on its anabolic effect to bone tissue and the ability to modulate immune responses with specific focus on osteoimmunology.
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Adalimumab in Crohn’s Disease: Tips and Tricks After 5 Years of Clinical Experience
G. Fiorino, H. Szabò, W. Fries, A. Malesci, L. Peyrin-Biroulet and S. Danese
Introduction: Three anti TNF-α agents have currently been approved for the treatment of moderate-to-severe or complicated Crohn’s disease (CD): infliximab, certolizumab and adalimumab. Infliximab is effective in CD, but for reasons linked to its chimeric structure, response to treatment may be lost overtime and as a result, it can sometimes be unable to provide long term durable treatment of CD. Adalimumab, a fully human anti TNF-α antibody, demonstrates similar treatment efficacy as infliximab and certolizumab, and can easily be self-administered at home.
Aim and Methods: A literature search in the Cochrane, MEDLINE, PUBMED, Ovid MEDLINER® and EMBASE databases has been performed on the efficacy, safety and the impact adalimumab has on the quality of life and natural history of CD. Abstracts presented at the DDW, UEGW and ECCO Congresses have also been reviewed as well as references from review articles, meta-analysis studies and published RCTs.
Results: Adalimumab induced remission of CD in 64% of patients, and maintained remission in more than 80% of initial responders. Adalimumab did not significantly increase the risk of adverse events compared with conventional medication up to 3 years of follow-up. Adalimumab reduces more than 50% the risk for hospitalisation and surgery due to CD. It is also effective for fistula closure, for the healing of the mucosa, and improving quality of life.
Conclusion: Adalimumab is effective in the induction and maintenance of clinical remission in CD and is generally well tolerated. It has been proved to have a positive impact by improving quality of life of patients, and reducing the need for hospitalisation and surgery due to CD. According to the European Crohn's and Colitis Organisation (ECCO), infliximab or adalimumab can be used for the treatment of fistulizing CD.
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Promising Targets for Anti-Hepatitis C Virus Agents
T. Yoshida, M. Kondoh and K. Yagi
Hepatitis C virus (HCV) infection is a serious global health problem, with 3-4 million new cases reported each year. Chronic HCV infection places 170 million people at risk of developing liver cirrhosis and hepatocellular carcinoma. However, difficulties in preparing HCV particles in vitro have delayed development of effective anti-HCV therapies. In 2005, Wakita et al. developed an in vitro method to prepare HCV particles, thereby enabling researchers to better understand the mechanism of HCV infection. Other recent advances include development of a virus-free system for evaluating HCV replication and the identification of HCV receptors, such as claudin-1 and occludin, that may serve as targets for anti-HCV drugs. In this review, we discuss recent findings in HCV infection research, including discovery of new potential targets for anti-HCV therapy.
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Chemopreventive Properties and Molecular Mechanisms of the Bioactive Compounds in Hibiscus Sabdariffa Linne
Hui-Hsuan Lin, Jing-Hsien Chen and Chau-Jong Wang
Hibiscus sabdariffa Linne is a traditional Chinese rose tea and has been effectively used in folk medicines for treatment of hypertension, inflammatory conditions. H. sabdariffa aqueous extracts (HSE) were prepared from the dried flowers of H. sabdariffa L., which are rich in phenolic acids, flavonoids and anthocyanins. In this review, we discuss the chemopreventive properties and possible mechanisms of various H. sabdariffa extracts. It has been demonstrated that HSE, H. sabdariffa polyphenol-rich extracts (HPE), H. sabdariffa anthocyanins (HAs), and H. sabdariffa protocatechuic acid (PCA) exert many biologic effects. PCA and HAs protected against oxidative damage induced by tert-butyl droperoxide (t-BHP) in rat primary hepatocytes. In rabbits fed cholesterol and human experimental studies, these studies imply HSE could be pursued as atherosclerosis chemopreventive agents as they inhibit LDL oxidation, foam cell formation, as well as smooth muscle cell migration and proliferation. The extracts also offer hepatoprotection by influencing the levels of lipid peroxidation products and liver marker enzymes in experimental hyperammonemia. PCA has also been shown to inhibit the carcinogenic action of various chemicals in different tissues of the rat. HAs and HPE were demonstrated to cause cancer cell apoptosis, especially in leukemia and gastric cancer. More recent studies investigated the protective effect of HSE and HPE in streptozotocin induced diabetic nephropathy. From all these studies, it is clear that various H. sabdariffa extracts exhibit activities against atherosclerosis, liver disease, cancer, diabetes and other metabolic syndromes. These results indicate that naturally occurring agents such as the bioactive compounds in H. sabdariffa could be developed as potent chemopreventive agents and natural healthy foods.