Mini-Reviews in Medicinal Chemistry

ISSN: 1389-5575

Mini-Reviews in Medicinal Chemistry
Volume 6, Number 8, August 2006

Contents

Glycogen Phosphorylase Inhibitors Pp. 845-857
Brad R. Henke and Steven M. Sparks
[Abstract]


Determinants of Specificity of Factor Xa Interaction with its Physiological Inhibitors Pp. 859-865
Alireza R. Rezaie
[Abstract]


p38 Mitogen-Activated Protein Kinase (MAPK) in Rheumatoid Arthritis Pp. 867-874
J. Westra and P.C. Limburg
[Abstract]


Potential for Discovery of Neuroprotective Factors in Serum and Tissue from Hibernating Species Pp. 875-884
Austin P. Ross and Kelly L. Drew
[Abstract]


Advances in Mitotic Inhibitors for Cancer Treatment Pp. 885-895
Ning Jiang, Xiaoxing Wang, Yali Yang and Wei Dai
[Abstract]


Leptin, Estrogens and Cancer Pp. 897-907
María del Carmen Maeso Fortuny, Buenaventura Brito Díaz and Antonio Cabrera de León
[Abstract]


S-Layer Proteins as Key Components of a Versatile Molecular Construction Kit for Biomedical Nanotechnology Pp. 909-920
B. Schuster, D. Pum, M. Sára and U.B. Sleytr
[Abstract]


New Zinc Binding Motifs in the Design of Selective Carbonic Anhydrase Inhibitors Pp. 921-936
Jean-Yves Winum, Andrea Scozzafava, Jean-Louis Montero and Claudiu T. Supuran
[Abstract]


Ligand Recognition by Drug-Activated Nuclear Receptors PXR and CAR:Structural, Site-Directed Mutagenesis and Molecular Modeling Studies Pp. 937-943
Antti Poso and Paavo Honkakoski
[Abstract]


Naturally Occurring NF- κB Inhibitors Pp. 945-951
Nguyen-Hai Nam
[Abstract]




Abstracts

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Glycogen Phosphorylase Inhibitors
Brad R. Henke and Steven M. Sparks

Type 2 diabetes is a complex metabolic disease with hyperglycemia as its recognizable hallmark. Hepatic glucose output is elevated in Type 2 diabetic patients, and evidence suggests drugs which lower hepatic glucose production are effective antihyperglycemic agents. Glycogenolysis, which is the release of monomeric glucose from its polymeric storage form called glycogen, is a key contributor to hepatic glucose output. Glycogen phosphorylase is the enzyme that catalyzes this process. This review covers advances in the design of small molecule inhibitors of this enzyme, their biological activity, and their potential as effective antihyperglycemic agents for the treatment of Type 2 diabetes.


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Determinants of Specificity of Factor Xa Interaction with its Physiological Inhibitors
Alireza R. Rezaie

Factor Xa (fXa) is the vitamin K-dependent serine protease of the prothrombinase complex (fXa, factor Va, negatively charged membrane, and calcium) which is responsible for the conversion of prothrombin to thrombin in the final stage of the coagulation cascade. The proteolytic activity of fXa in plasma is primarily regulated by three physiological inhibitors, antithrombin (AT), protein Z-dependent protease inhibitor (ZPI) and tissue factor pathway inhibitor (TFPI). The first two inhibitors belong to the serpin family of plasma inhibitors, both of which require cofactors for their effective interaction with fXa. Thus, the AT interaction with the heparin-like glycosaminoglycans on the surface of the endothelium, and the ZPI complex formation with protein Z on membrane phospholipids is required for the physiological regulation of fXa by both serpins. On the other hand, TFPI is a slow and tight-binding, Kunitz type inhibitor that is capable of rapidly inhibiting fXa independent of a cofactor. This article will review the structural features that enable fXa to specifically interact with these three inhibitors under different conditions.


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p38 Mitogen-Activated Protein Kinase (MAPK) in Rheumatoid Arthritis
J. Westra and P.C. Limburg

The importance of p38 MAPK inhibitors as new drug for rheumatoid arthritis is reflected by the large number of compounds that has been developed over the last years. In this review new insights such as non-stressful activation of p38 MAPK, and the role of p38 MAPK in regulation of NF-κB recruitment are also discussed.


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Potential for Discovery of Neuroprotective Factors in Serum and Tissue from Hibernating Species
Austin P. Ross and Kelly L. Drew

Hibernation is a unique phenotype displayed by a phylogenetically diverse group of organisms including several species of mammals and one species of primate. Here we review evidence for blood and tissue borne signaling molecules in hibernating animals, achievements in isolating and characterizing these molecules, and potential medicinal applications.


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Advances in Mitotic Inhibitors for Cancer Treatment
Ning Jiang, Xiaoxing Wang, Yali Yang and Wei Dai

Based on their mechanism of action, anti-tumor drugs that target the cell cycle can be generally divided into three categories, namely, blocking DNA synthesis, causing DNA damage, and disrupting mitotic processes. In terms of mitotic inhibitors, most compounds used in the clinic impair the normal function of mitotic spindles by targeting tubulins, basic building blocks of microtubules. In vivo, these compounds often exhibit significant side effects, thus limiting their efficacy. Mitotic processes are under tight control through surveillance mechanisms commonly termed checkpoints. Defects in the regulation of these checkpoints often result in genomic instability, which predisposes the cell to malignant transformation. As cancer is the consequence of uncontrolled cell division, great efforts have been devoted to discover drugs that target mitosis, thereby halting cell division and inducing mitotic catastrophe with minimal cytotoxicity to non-dividing or normally dividing cells. This review primarily focuses on mitotic proteins that have been explored as new targets for anti-cancer drug development during the past decade.


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Leptin, Estrogens and Cancer
María del Carmen Maeso Fortuny, Buenaventura Brito Díaz and Antonio Cabrera de León

Obesity is a state of leptin resistance in which the membrane leptin receptor and the JAK-STAT pathway are blocked. This leads to increased intracellular concentrations of lipid metabolites, increased non-oxidative metabolism by adipocytes, and stimulation of the cell estrogen cycle. These factors are potentially oncogenic via the shared mitogen-activated protein kinase (MAPK), mitogen/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK) cellular pathways.


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S-Layer Proteins as Key Components of a Versatile Molecular Construction Kit for Biomedical Nanotechnology
B. Schuster, D. Pum, M. Sára and U.B. Sleytr

Surface (S)-layer proteins and S-layer fusion proteins incorporating functional sequences, self-assemble into monomolecular lattices on solid supports and on various lipid structures. Based on these S-layer proteins, supramolecular assemblies can be constructed which are envisaged for label-free detection systems, as affinity matrix, as anti-allergic immuno-therapeutics, as membrane protein-based screening devices, and as drug targeting and delivery systems.


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New Zinc Binding Motifs in the Design of Selective Carbonic Anhydrase Inhibitors
Jean-Yves Winum, Andrea Scozzafava, Jean-Louis Montero and Claudiu T. Supuran

The carbonic anhydrases (CAs, EC 4.2.1.1) are ubiquitous zinc enzymes which catalyze a very simple physiological reaction, the interconversion between carbon dioxide and the bicarbonate ion, and are involved in physiological and pathological processes. The different isozymes have been considered as important targets for inhibitors with clinical applications. Several sulfonamide carbonic anhydrase inhibitors (CAIs) were used for decades as diuretics, anti-glaucoma, anti-epileptic, anti-ulcer agents, or as drugs for treating other neurological/neuromuscular disorders, whereas presently several such agents still find wide applications in therapy, mainly as topically acting anti-glaucoma drugs, anti-cancer, or anti-obesity agents. Although sulfonamides were considered the moiety par excellence to coordinate the catalytic zinc and for designing potent CAIs, in recent years related functional groups such as sulfamate, sulfamide and others have proven to be successful in the design of selective CAIs. The present review will deal with these different zinc binding functions recently reported in literature.


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Ligand Recognition by Drug-Activated Nuclear Receptors PXR and CAR:Structural, Site-Directed Mutagenesis and Molecular Modeling Studies
Antti Poso and Paavo Honkakoski

Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are the principal regulators of drug/xenobiotic disposition and toxicity. These nuclear receptors display considerable cross-regulation of their target genes, and species-specific, yet promiscuous activation by a large number of structurally dissimilar ligands. Activation of PXR and/or CAR will frequently result in enhanced drug metabolism, disturbances in homeostasis of endogenous substances, and increased toxicity. Thus, understanding, measurement and prediction of ligand-elicited activation of PXR and CAR receptors is of utmost importance for the drug development process. In this mini-review, we will review the recent elucidation of structural properties of PXR and CAR, the molecular determinants of their ligand and species specificities and progress made in in silico models for identification of PXR and CAR activators.


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Naturally Occurring NF- κB Inhibitors
Nguyen-Hai Nam

NF-κB is a ubiquitous and well-characterised protein responsible for the regulation of complex phenomena, with a pivotal role in controlling cell signalling in the body under certain physiological and pathological conditions. Among other functions, NF-κB controls the expression of genes encoding the pro-inflammatory cytokines (e. g., IL-1, IL-2, IL-6, TNF-α , etc.), chemokines (e. g., IL-8, MIP-1α , MCP1, RANTES, eotaxin, etc.), adhesion molecules (e. g., ICAM, VCAM, E-selectin), inducible enzymes (COX-2 and iNOS), growth factors, some of the acute phase proteins, and immune receptors, all of which play critical roles in controlling most inflammatory processes. Since NF-κB represents an important and very attractive therapeutic target for drugs to treat many inflammatory diseases, including arthritis, asthma, and the auto-immune diseases, most attention has been paid in the last decade to the identification of compounds that selectively interfere with this pathway. Recently, a great number of plant-derived substances have been evaluated as possible inhibitors of the NF-κB pathway. These include a wide range of compound classess, such as lignans (manassantins, (+)-saucernetin, (-)-saucerneol methyl ether), sesquiterpenes (costunolide, parthenolide, celastrol, celaphanol A), diterpenes (excisanin, kamebakaurin), triterpenes (avicin, oleandrin), polyphenols (resveratrol, epigallocatechin gallate, quercetin), etc. In this mini-review we will discuss the medicinal chemistry of these compounds with regards to the NF-κB inhibition.