Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 14, Number 19, 2007

Contents


Targeting the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Module for Acute Myelogenous Leukemia Therapy: From Bench to Bedside Pp. 2009-2023
A.M. Martelli, P.L. Tazzari, C. Evangelisti, F. Chiarini, W.L. Blalock, A.M. Billi, L. Manzoli, J.A. McCubrey and L. Cocco
[Abstract]


Molecular Target-Guided Tumor Therapy with Natural Products Derived from Traditional Chinese Medicine Pp. 2024-2032
Thomas Efferth, Yu-jie Fu, Yuangang Zu, Günter Schwarz, Venkata Sai Badireenath Konkimalla and Michael Wink
[Abstract]


Discovery and Development of ATPase Inhibitors of DNA Gyrase as Antibacterial Agents Pp. 2033-2047
Marko Oblak, Miha Kotnik and Tom Solmajer
[Abstract]


Viral Infection – A Cure for Type 1 Diabetes? Pp. 2048-2052
Edith Hintermann and Urs Christen
[Abstract]


HTR2A Gene Variants and Psychiatric Disorders: A Review of Current Literature and Selection of SNPs for Future Studies Pp. 2053-2069
Alessandro Serretti, Antonio Drago and Diana De Ronchi
[Abstract]


Anti-Arrhythmic Properties of N-3 Poly-Unsaturated Fatty Acids (n 3 PUFA) Pp. 2070-2080
Federico Lombardi and Paolo Terranova
[Abstract]


Current Treatments of Primary Sclerosing Cholangitis Pp. 2081-2094
M. Vacca, M. Krawczyk, M. Petruzzelli, R.C. Sasso, K.J. van Erpecum, G. Palasciano, G.P. vanBerge-Henegouwen, A. Moschetta and P. Portincasa
[Abstract]


Estrogen(s) and Analogs as a Non-Immunogenic Endogenous Ligand in Targeted Drug/DNA Delivery Pp. 2095-2109
Shivani Rai, Rishi Paliwal, Bhuvaneshwar Vaidya, Prem N. Gupta, Sunil Mahor, Kapil Khatri, Amit K. Goyal, Amit Rawat and S.P. Vyas
[Abstract]




Abstracts


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Targeting the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Module for Acute Myelogenous Leukemia Therapy: From Bench to Bedside
A.M. Martelli, P.L. Tazzari, C. Evangelisti, F. Chiarini, W.L. Blalock, A.M. Billi, L. Manzoli, J.A. McCubrey and L. Cocco

The phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B, PKB)/mammalian Target Of Rapamycin (mTOR) signaling pathway plays a critical role in many cellular functions which are elicited by extracellular stimuli. However, constitutively active PI3K/Akt/mTOR signaling has also been firmly established as a major determinant for cell growth, proliferation, and survival in an wide array of human cancers. Thus, blocking the PI3K/AKT/mTOR signal transduction network could be an effective new strategy for targeted anticancer therapy. Pharmacological inhibitors of this signaling cascade are powerful antineoplastic agents in vitro and in xenografted models of tumors, and some of them are now being tested in clinical trials. Recent studies showed that PI3K/Akt/mTOR axis is frequently activated in acute myelogenous leukemia (AML) patient blasts and strongly contributes to proliferation, survival, and drug-resistance of these cells. Both the disease-free survival and overall survival are significantly shorter in AML cases with PI3K/Akt/mTOR upregulation. Therefore, this signal transduction cascade may represent a target for innovative therapeutic treatments of AML patients. In this review, we discuss the possible mechanisms of activation of this pathway in AML cells and the downstream molecular targets of the PI3K/Akt/mTOR signaling network which are important for blocking apoptosis, enhancing proliferation, and promoting drug-resistance of leukemic cells. We also highlight several pharmacological inhibitors which have been used to block this pathway for targeted therapy of AML. These small molecules induce apoptosis or sensitize AML cells to existing drugs, and might be used in the future for improving the outcome of this hematological disorder.


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Molecular Target-Guided Tumor Therapy with Natural Products Derived from Traditional Chinese Medicine
Thomas Efferth, Yu-jie Fu, Yuangang Zu, Günter Schwarz, Venkata Sai Badireenath Konkimalla and Michael Wink

A tremendous interest exists in the Western world in Traditional Chinese Medicine (TCM) with rapidly increasing export rates of TCM products from China to Europe and USA. This led to a national decision of the Chinese government to implement a “Plan for the Modernization of Chinese Medicine”. Concerning the use of Chinese medicinal herbs, two major directions can be distinguished. One field is phytochemistry and pharmacognosy. Secondary metabolites isolated from Chinese plants can be easily subjected to pharmacological, molecular biological, and pharmacogenomic analyses using methods of modern cell and molecular biology as exemplified for camptothecin from Camptotheca acuminata in the present review. The second field of interest is phytomedicine. Standardized international quality guidelines help to improve quality, safety and efficacy of Chinese medicinal herbs. Sustainability of natural products from TCM can be reached by breeding high-yield varieties or by biotechnological approaches. In the long term, natural products from TCM can contribute to the development of molecular target-guided therapies and individualized treatment strategies.


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Discovery and Development of ATPase Inhibitors of DNA Gyrase as Antibacterial Agents
Marko Oblak, Miha Kotnik and Tom Solmajer

DNA gyrase is an attractive and well established target for the development of antibacterial agents. This bacterial enzyme, whose biological function is to control the topological state of DNA molecules, consists of two catalytic subunits; GyrA is responsible for DNA breakage and reunion, while the subunit GyrB contains the ATP-binding site. Coumarins and cyclothialidines are natural products that inhibit the ATPase activity of DNA gyrase by blocking the binding of ATP to subunit GyrB. The mechanism of action of these compounds was exhaustively characterized by biochemical methods and supported by protein crystallography. The abundance of crystallographic data on the N-terminal domain of GyrB in its complexes with various ligands has enabled the structure-based design of novel efficient chemotypes as inhibitors of the ATPase domain. This review summarizes the discovery of ATPase inhibitors of DNA gyrase B in the last decade and their development as potential antibacterial agents.


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Viral Infection – A Cure for Type 1 Diabetes?
Edith Hintermann and Urs Christen

Autoimmune diseases are thought to arise as a detrimental combination of genetic predisposition and environmental factors. Because of their potential for direct cellular damage and causing extensive inflammation, viruses are one of the major candidates for triggering autoimmunity. Although there is epidemiological evidence, direct proof for viruses as causative agents for autoimmune disease is hard to get since most viruses have been eliminated from the system by the time of diagnosis. However, evidence from various animal models suggests that viruses can indeed initiate or accelerate autoimmune diseases, such as type 1 diabetes or experimental allergic encephalomyelitis. In contrast, viruses have been also demonstrated to abrogate autoimmune disease in animal models. These observations might offer one explanation why increased frequencies of allergies and autoimmune diseases parallel with higher hygienic standards. This review reflects on the epidemiological evidence for the association of viruses with autoimmune diseases, the experimental evidence for viruses to abrogate an ongoing autoimmune destruction and evaluates the possibility for a therapeutic application.


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HTR2A Gene Variants and Psychiatric Disorders: A Review of Current Literature and Selection of SNPs for Future Studies
Alessandro Serretti, Antonio Drago and Diana De Ronchi

Variants at the gene encoding for the 5-hydrosytryptamine (serotonin) receptor 2A (HTR2A) have been associated with many psychiatric disorders such as schizophrenia, mood disorders, attention deficit hyperactivity disorder, suicide, anxiety disorders, obsessive–compulsive disorder, eating disorders, and Alzheimer’s disease. The studied SNPs differ across studies, in the present review we focused on available evidence with the aim of identifying the overall phenotypic profile of HTR2A variant carriers. We then extensively analyzed all SNPs of the HTR2A gene with criteria of frequency, haplotype blocks, previous evidence, functionality in order to obtain a list of suitable SNPs for future studies that properly cover all possible genetic control of the HTR2A gene.

Genetic association studies report conflicting and generally negative results. Most replicated data suggest C allele of the 102 T/C and Tyr452 variants as risk factor for psychosis and antipsychotic response, but the number of not replicating studies does not allow to draw any definite conclusion. Moreover their impact as risk factors is very small. In the other investigated psychiatric fields, evidence shows no involvement or at least a small and not replicated role for HTR2A gene variants. Conflicting and negative results could be due to a real marginal role of this receptor gene variants, or it could be caused by a lack of gene coverage of investigated SNPs. We suggest a wider investigation of the HTR2A gene to better understand its role in psychiatric disorders, preferably complemented with the use of proteomic or metabolomic approaches.


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Anti-Arrhythmic Properties of N-3 Poly-Unsaturated Fatty Acids (n 3 PUFA)
Federico Lombardi and Paolo Terranova

Omega-3 fatty acids (Poly-Unsaturated Fatty Acids or PUFA n-3) have been initially found to reduce plasma levels of triglycerides and to increase levels of high-density lipoprotein in patients with marked hypertriglyceridemia. However, in both bench research studies and clinical trials, omega-3 fatty acid intake has recently been associated with an anti-arrhythmic efficacy. At experimental level, n-3 PUFA administration produces several actions on ionic channels regulating transmembrane action potential. At clinical level, the most significant finding was the reduction in the incidence of sudden death in survivors of MI in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevention trial and the subsequent recommendation for administration of fish oil as part of the post-infarction regimen in European guidelines. More recently, Omega-3 fatty acids administration has been associated with a lower incidence of atrial fibrillation in patients who underwent cardiac surgery. Contrasting results have been instead reported in patients with implantable cardioverter defibrillators. This article reviews in detail the basic and clinical research studies of fish oil as an anti-arrhythmic entity, the types of arrhythmias that have been beneficially affected by fish oil administration, and the presumed and known mechanisms by which the beneficial actions are exerted.


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Current Treatments of Primary Sclerosing Cholangitis
M. Vacca, M. Krawczyk, M. Petruzzelli, R.C. Sasso, K.J. van Erpecum, G. Palasciano, G.P. vanBerge-Henegouwen, A. Moschetta and P. Portincasa

Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic disease characterized by hepatic inflammation and obliterative fibrosis, resulting in both intra- and extra-hepatic bile duct strictures. End-stage liver disease and bile duct carcinoma represent frequent complications. Incidence and prevalence of PSC in USA have been recently estimated as 0.9 per 100,000 person-years, and 1-6 per 100,000 person-years, respectively. Major diagnostic criteria include the presence of multifocal strictures, beadings of bile ducts, and compatible biochemical profile, once excluded secondary causes of cholangitis. Since the aetiology of PSC remains poorly defined, medical therapy is currently limited to symptom improvement and prolonged survival. Ursodeoxycholic acid (UDCA), corticosteroids and immunosuppressants have been proposed alone or in combination to improve the clinical outcome. In selected cases, surgical or endoscopic procedures need to be considered. Orthotopic liver transplantation (OLT) is at the moment the only definitive approach although disease relapse has been reported.

In this article the state of the art in PSC treatment and future promises in this field are reviewed.


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Estrogen(s) and Analogs as a Non-Immunogenic Endogenous Ligand in Targeted Drug/DNA Delivery
Shivani Rai, Rishi Paliwal, Bhuvaneshwar Vaidya, Prem N. Gupta, Sunil Mahor, Kapil Khatri, Amit K. Goyal, Amit Rawat and S.P. Vyas

The maximum therapeutic potentials of pharmacologically active molecules are generally not attained due to their non specific delivery. Ligands associated with drug or delivery system through which it is delivered provide navigation and direction to the carrier system(s) so as to reach and release bioactive(s) at the desired site of action in a optimum therapeutic concentration vis a vis minimizing the undesired side effects associated with non specific delivery. Many ligands employed and implicated in targeted drug delivery have been reportedly found to be mild to strong immunogenic. Hence, their potential utility is considered to be compromised in achieving concept of magic bullet. Therefore endogenous ligand (bio self molecules) based drug/DNA delivery may be a better alternative they being biocomponents so are non-immunogenic and biocompatible per se. Estrogens and their receptors are over expressed in the several pathophysiological conditions including cardiovascular, osteoarthritis and cancer of prostate and ovaries etc. The selective high density of such portal may be utilized for targeting such estrogen receptor rich sites. The several scientific communities from various fields of specialization of science have explored estrogen(s) and their analogs for the purpose of targeting of bioactive(s) either by preparing estrogen-drug conjugates of using estrogens as site-directing ligands attached with various carrier system(s). This review presents an exhaustive account of how hormones especially estrogens and their derivatives could be used for site-specific delivery of bioactive(s), as diagnostic agents and also the future prospects of these bioligands in controlled and targeted clinical pharmacology. Estrogen-drug conjugates and various carrier systems that utilized estrogens as ligands for site-specific delivery have been reviewed and are discussed in detail.