Current Medicinal Chemistry

ISSN: 0929-8673

Current Medicinal Chemistry
Volume 13, Number 10, 2006

Contents


Rational Drug Design of Selective ε Opioid Receptor Agonist TAN-821 and Antagonist TAN-1014 Pp. 1109-1118
H. Fujii and H. Nagase
[Abstract]


Chemistry and Biology of Chromatin Remodeling Agents: State of Art and Future Perspectives of HDAC Inhibitors Pp.1119-1139
Manuela Rodriquez, Maurizio Aquino, Ines Bruno, Giovanni De Martino, Maurizio Taddei and Luigi Gomez-Paloma
[Abstract]


Roles of Glycans and Glycopeptides in Immune System and Immune-Related Diseases Pp. 1141-1147
Xiao-Lian Zhang
[Abstract]


Targeting Cytokines of the Interleukin-12 Family in Autoimmunity Pp. 1149-1156
Bok Yun Kang and Tae Sung Kim
[Abstract]


Aminolevulinic Acid Derivatives and Liposome Delivery as Strategies for Improving 5-Aminolevulinic Acid-Mediated Photodynamic Therapy Pp. 1157-1168
Adriana Casas and Alcira Batlle
[Abstract]


Choline Kinase: An Important Target for Cancer Pp. 1169-1186
S. Janardhan, P. Srivani and G. Narahari Sastry
[Abstract]


Reactive Oxygen Species-Induced Gastric Ulceration: Protection By Melatonin Pp. 1187-1202
Debashis Bandyopadhyay and Aindrila Chattopadhyay
[Abstract]


Antidiabetic Agents from Medicinal Plants Pp. 1203-1218
Mankil Jung, Moonsoo Park, Hyun Chul Lee, Yoon-Ho Kang, Eun Seok Kang, and Sang Ki Kim
[Abstract]


The Mercaptopyruvate Pathway in Cysteine Catabolism: A Physiologic Role and Related Disease of the Multifunctional 3 Mercaptopyruvate Sulfurtransferase Pp. 1219-1230
Noriyuki Nagahara and Nori Sawada
[Abstract]



Abstracts


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Rational Drug Design of Selective ε Opioid Receptor Agonist TAN-821 and Antagonist TAN-1014
H. Fujii and H. Nagase

Dβ-Endorphin (β-EP) is generally classified as a μ and δ opioid receptor agonist but is also an agonist of the ε opioid receptor. Although several selective agonists and antagonists for μ, δ, and κ opioid receptors are known, selective ε receptor agonists or antagonists have not been reported for some time. Recently, we designed and synthesized the selective ε receptor agonist, 17-(cyclopropylmethyl)-4,5α-epoxy-3,6β-dihydroxy-6,14 endoethenomorphinan-7α-[N-methyl-N-phenethyl]carboxamide (TAN-821), and the selective ε receptor antagonist, 17-(cyclopropylmethyl)-4,5α-epoxy-6β,
21-epoxymethano-3-hydroxy-6,14-endoe-thenomorphinan-7α-(N-phenethyl)carboxamide (TAN-1014). TAN-821 stimulated binding of the non-hydrolyzable guanosine 5’-triphosphate analogue, guanosine 5’-(γ-thio)-triphosphate (GTPγS), to the mouse pons/medulla membrane via activation of the ε receptor. Moreover, TAN-821 given intracerebroventricularly (i.c.v.) produced marked, long-lasting, and dose-dependent antinociception in tail-flick and hot-plate tests. This antinociception induced by i.c.v. administered TAN-821 was blocked by i.c.v. pretreatment with the ε opioid receptor partial agonist β-EP (1-27), but not the μ opioid receptor antagonist β-FNA, the δ opioid receptor antagonist NTI, or the κ opioid receptor antagonist nor-BNI. On the other hand, i.c.v. injection of TAN-1014 alone produced no antinociception, and i.c.v. pretreatment with TAN-1014 attenuated the antinociception induced by i.c.v β-EP. These results suggest that TAN-821 and TAN-1014 are respectively a selective ε receptor agonist and antagonist and that they may be useful tools for investigating the pharmacological properties of the ε opioid receptor.


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Chemistry and Biology of Chromatin Remodeling Agents: State of Art and Future Perspectives of HDAC Inhibitors Manuela Rodriquez, Maurizio Aquino, Ines Bruno, Giovanni De Martino, Maurizio Taddei and Luigi Gomez-Paloma

Chromatin remodeling is a fundamental phenomenon in the life of eukaryotic cells, bearing implications to numerous physiological and pathological phenomena. This review outlines the chemistry of natural and synthetic agents endowed with the ability to interfere with such biological function, with a particular emphasis on histone deacetylase (HDAC) inhibitors. Other aspects covered in this article comprise structure activity relationships (SAR) and modes of action at molecular level, including the description of crystal structures of enzyme-inhibitor complexes.


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Roles of Glycans and Glycopeptides in Immune System and Immune-Related Diseases
Xiao-Lian Zhang

Almost all of the key molecules in organisms involved in the innate and adaptive immune response (including immunoglobulins, cytokines and cytokine receptors, complements, CD molecules, adhesions, T-cell receptors and major histocompatibility complex molecules) are glycoproteins. Besides, foreign antigens, such as many viral envelope proteins, are glycoproteins too. Carbohydrates attached to proteins or peptides are classified by the nature of their linkages to the protein, mostly as either N-linked (N-acetylglucosamine to asparagines) or O-linked (N-acetylgalactosamine to serine or threonine) oligosaccharides. The glycans have three major roles: firstly, the sugars confer stability on the proteins to which they are attached, protecting them from proteases and non-specific protein-protein interactions. Secondly, glycans play key roles in signal transduction, control of cell development and differentiation. Thirdly, specific regions of the oligosaccharide chains provide recognition epitopes, which influence innate and adaptive immune responses. Glycopeptides not only provide specific oligosaccharides, but also have specific information of amino acids sequences. The glycans and glycopeptides not only influence the structure and functions of immune molecules, but also influence the immune response. In addition, changes in glycans or glycopeptides may have a significant role in a variety of human immune-related diseases, such as rheumatoid, autoimmune disease, Wiskott-Aldrich syndrome, infection disease, cancer, etc. In this article, the roles of N-, O-glycans and glycopeptides in immune system and immune-related diseases are discussed. The potential therapeutic significance of the information is also mentioned.


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Targeting Cytokines of the Interleukin-12 Family in Autoimmunity
Bok Yun Kang and Tae Sung Kim

In the past, autoimmunity was thought to be mediated by antibodies and immune complexes. It has now become clear that many autoimmune diseases, especially tissue specific, are T cell-mediated, or at least T cell-dependent. The pathogenesis of cell-mediated autoimmune diseases, including multiple sclerosis, uveitis, diabetes, arthritis, and others, is now thought to be, in a large measure, driven by interferon-γ-producing, antigen-specific T cells, which are polarized toward the T helper type 1 (Th1) phenotype. Interleukin (IL)-12 and the more recently discovered IL-23 and IL-27 constitute a unique family of structurally-related, heterodimeric cytokines, which regulate cell-mediated immune responses and Th1-type inflammatory reactions. Thus, these cytokines may have a central role in the development and progression of cell-mediated autoimmune diseases. Therefore, pharmacologically targeting cytokines of the IL-12 family would be useful in the modulation of several autoimmune diseases. This review summarizes the recent findings concerning IL-12 family cytokine-mediated autoreactive inflammatory responses, and also describes some possible therapeutic interventions, including medicinal compounds at mitigating autoimmune inflammation.


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Aminolevulinic Acid Derivatives and Liposome Delivery as Strategies for Improving 5-Aminolevulinic Acid-Mediated Photodynamic Therapy
Adriana Casas and Alcira Batlle

Photodynamic Therapy employing 5-aminolevulinic acid (ALA) as a precursor of the photosensitizer Protoporphyrin IX has become a promising approach to treat superficial cancers. However, the hydrophilic nature of the ALA molecule somewhat limits the penetration through the skin as well as all cell membranes. Different attempts are currently under investigation to enhance ALA penetration, such as the development of new synthetic and more lipophilic molecules derived from ALA and the incorporation of ALA into lipophilic vehicles such as liposomes. Among the new synthesized molecules, we can find ALA esters, ALA aminoacid derivatives and ALA dendrimers. In general, there is consensus that the promising results obtained in vitro with ALA esters cannot be reproduced in vivo. However, ALA methyl ester (1) has been widely used for treatment of skin malignancies and ALA hexyl ester (15) proved to be more powerful than ALA in bladder imaging. ALA aminoacid derivatives have been designed to use specific cellular aminopeptidases to targeting tumors, and it was shown that they can be metabolized to ALA with some specificity.


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Choline Kinase: An Important Target for Cancer
S. Janardhan, P. Srivani and G. Narahari Sastry

Choline kinase (ChoK) is a cytosolic enzyme present in various tissues, whcih catalyzes the phosphorylation of choline to form phosphorylcholine (PCho) in the presence of ATP and magnesium. ChoK is important for the generation of two major membrane phospholipids, phosphatidylcholine (PC) and sphingomyelin (SM) and subsequently for the cell division. ChoK plays a vital role in cell signaling pathways and regulation of cell growth along with PCho involved in malignant transformation through ras oncogenes in different cancers such as breast, lung, colon, prostate, neuroblastoma, hepatic lymphomas, meningiomas and diverse murine tumours. The Ras effectors serine/threonine kinase (Raf-1), the Ral-GDP dissociation stimulator (Ral-GDS) and the phosphatidylinositol 3-kinase (PI3K) are involved in the activation of ChoK during tumorigenesis. ChoK gene induction seems to be associated with certain cell stress or cell defense. Nowadays, RNAi appear to be one of the most promising routes in the cancer therapy. The anticancer potential of both stable expression of siRNAs and their high sequence specificity by RNAi mediated suppression of oncogenic ras in human pancreatic carcinoma, human melanomas and ovarian cancer has been observed. It has an important role in sequence specific post-transcriptional gene silencing mechanism. Presently, the crystal structure of Caenorhabditis elegans choline kinase A-2 (ChoKA-2) is available, which may be useful for comparative modeling of human ChoK and further modeling studies. The present review aims at the general overview of importance, expression, structure, progress in molecular modeling, active site analysis and inhibitors of ChoK. It also highlights the recent role of ChoK in various types of Ras-dependent and Ras-independent carcinogenesis.


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Reactive Oxygen Species-Induced Gastric Ulceration: Protection By Melatonin
Debashis Bandyopadhyay and Aindrila Chattopadhyay

Gastric hyperacidity and ulceration of the stomach mucosa due to various factors are serious health problems of global concern. Although the mechanism of acid secretion from the parietal cells is now well understood, the processes involved in gastric ulceration are still not clear. Among the various causes of gastric ulceration, lesions caused by stress, alcohol consumption, Helicobacter pylori and due to use of non-steroidal anti-inflammatory drugs have been shown to be mediated largely through the generation of reactive oxygen species, especially the hydroxyl radical. A number of excellent drugs, developed over the decades, have proven useful in controlling hyperacidity and ulceration although their long-term use is reported to be associated with various side effects. Hence the investigations continue with an objective to find a compound possessing anti-secretory, anti-ulcer and antioxidant properties which will serve as a therapeutic agent to reduce gastric hyperacidity and ulcers. This article describes the role of reactive oxygen species in gastric ulceration, briefly presents a note on the currently available drugs controlling them, and focuses on the role of melatonin, a pineal secretory product, in protecting against gastric lesions. In experimental studies, melatonin has been shown to be effective in reducing mucosal breakdown and ulcer formation in a wide variety of situations. Additionally, the low toxicity of melatonin supports further investigation of this molecule as a promising gastro-protective agent. Finally, we include a commentary on how melatonin research with respect to gastric pathophysiology can move forward with a view to eventually using this indole as a therapeutic agent alone or in combination with the existing drugs to control gastric ulceration in humans in order to increase their efficacy and / or to reduce their side effects.


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Antidiabetic Agents from Medicinal Plants
Mankil Jung, Moonsoo Park, Hyun Chul Lee, Yoon-Ho Kang, Eun Seok Kang, and Sang Ki Kim

Currently available therapeutic options for non–insulin-dependent diabetes mellitus, such as dietary modification, oral hypoglycemics, and insulin, have limitations of their own. Many natural products and herbal medicines have been recommended for the treatment of diabetes. The present paper reviews medicinal plants that have shown experimental or clinical antidiabetic activity and that have been used in traditional systems of medicine; the review also covers natural products (active natural components and crude extracts) isolated from the medicinal plants and reported during 2001 to 2005. Many kinds of natural products, such as terpenoids, alkaloids, flavonoids, phenolics, and some others, have shown antidiabetic potential. Particularly, schulzeines A, B, and C, radicamines A and B, 2,5-imino-1,2,5-trideoxy-L-glucitol, β-homofuconojirimycin, myrciacitrin IV, dehydrotrametenolic acid, corosolic acid (Glucosol™), 4-(α-rhamnopyranosyl)ellagic acid, and 1,2,3,4,6-pentagalloylglucose have shown significant antidiabetic activities. Among active medicinal herbs, Momordica charantia L. (Cucurbitaceae), Pterocarpus marsupium Roxb. (Leguminoceae), and Trigonella foenum graecum L. (Leguminosae) have been reported as beneficial for treatment of type 2 diabetes.


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The Mercaptopyruvate Pathway in Cysteine Catabolism: A Physiologic Role and Related Disease of the Multifunctional 3 Mercaptopyruvate Sulfurtransferase
Noriyuki Nagahara and Nori Sawada

The conversion of cysteine to 3-sulfino-alanine is a major pathway in cysteine catabolism. Cysteine dioxygenase catalyzes the reaction and dietary intake of the essential amino acid methionine and the semi-essential amino acid cysteine increases the level of this enzyme by suppressing enzyme degradation via polyubiquitination.

The production of cellular antioxidants such as glutathione, thioredoxin, and their families is important in cysteine metabolism, and these cellular antioxidants have critical roles in the maintenance of the cellular redox status. The mercaptopyruvate pathway, in which cysteine or aspartate transaminase catalyzes the transamination from cysteine to 3-mercaptopyruvate and then 3-mercaptopyruvate sulfurtransferase catalyzes the transsulfuration from 3-mercaptopyruvate to pyruvate, also contributes to maintein the cellular redox. 3-Mercaptopyruvate sulfurtransferase serves as an antioxidant protein: when the enzyme is exposed to stoichiometric amounts of the oxidant hydrogen peroxide, it is inhibited via the formation of low redox sulfenate at the catalytic site cysteine. On the other hand, activity is restored by the reductant dithiothreitol or reduced thioredoxin.

3-Mercaptopyruvate sulfurtransferase also detoxifies cyanide via transsulfuration from a stable persulfide at the catalytic site cysteine, a reaction intermediate, suggesting that cyanide detoxification is not necessarily an enzymatic reaction. Furthermore, a congenital defect of the enzyme causes mercaptolactate-cysteine disulfiduria associated with or without mental retardation, although the pathogenesis remains unclear. These facts suggest that 3-mercaptopyruvate sulfurtransferase has physiologic roles as an antioxidant and a cyanide antidote; is essential for neural function, and participates in cysteine degradation.