Current Bioactive Compounds

Current Bioactive Compounds

Volume 2, Number 4, December 2006


Contents

Recent Advances in Thrombopoietic Small Molecules Pp. 395-408
Ryuichi Sakai, Takanori Nakamura and Hisao Kamiya
[Abstract]


Sensing Reactive Oxygen and Nitrogen Species Using Selective Fluorescent Probes Pp. 409-430
Nobuaki Soh and Toshihiko Imato
[Abstract]


Interferons: Mechanisms, Biological Activities and Survey of their Use in Human Diseases Pp. 431-444
Dalia Obeid and Brigitte Bauvois
[Abstract]


Preparation and Oxidation Chemistry of the Catechol Estrogens: Relevance to Estrogen-Related Carcinogenesis and Potential for Drug Design Pp. 445-451
Alessandro Pezzella, Liliana Lista, Alessandra Napolitano and Marco d’Ischia
[Abstract]


Bioactive Compounds

Anti-Cancer/Anti-Tumor Pp. 453

Anti-Diabetic Pp. 469

Anti-Viral Pp. 471

Anti-Inflammatory Pp. 475

Anti-Malarial Pp. 479

Anti-Microbial Pp. 480

Anti-Oxidant Pp. 485

Cardiovascular-Related Pp. 487

Central Nervous System-Related Pp. 489

Cholesterol-Lowering Pp. 490

Anti-Obesity Pp. 491

Anti-Hypertensive Pp. 492

Enzyme Inhibitors Pp. 493

Immunomodulatory Pp. 500

Alzheimer’s Disease Related Pp. 503

Other Activities Pp. 504




Abstracts

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Recent Advances in Thrombopoietic Small Molecules
Ryuichi Sakai, Takanori Nakamura and Hisao Kamiya

Proliferation and differentiation of stem cells are regulated by plural cytokines. One of those cytokines, thrombopoietin (TPO), a 332 amino acid protein, stimulates proliferation of hematopoietic stem cells, and differentiates them into megakaryocytic progenitor cells which in turn transform into megakaryocytes, direct precursors of platelets. Dysfunction in platelet production - thrombocytopenia, which can contribute to further bleeding complications and mortality, is often accompanied by cancer chemotherapy and/or radiation therapy. Since platelet transfusion is the only treatment for thrombocytopenia, drugs that possess TPO-like action, and that are administered orally, would be of great clinical benefit. Recently, a number of studies dealing with discovery and biological actions of non-peptide small molecule TPO mimics have been disclosed. These studies lead to a general understanding that small aromatic compounds can be true agonists for TPO receptors with full efficacy identical to that of TPO. Structure-activity relationship studies and pharmacological investigations with these molecules started to reveal pharmacophore and mechanisms of actions. However, exact mechanisms showing how the receptor is activated by small molecules are still to be investigated. Several different classes of molecules identified as c-Mpl agonists, including benzodiazepine, hydrazinonaphthalenes, substituted thiophenes, or thiazoles, may suggest plural pharmacophores and mechanisms underlying activation of the receptor. Recently a fungal product xanthocillin was discovered to have this activity, showing natural products can be an interesting source for the new structure. Further recruitment of diverse types of molecules with this activity will facilitate deeper insight into the mechanism of activation on a molecular basis. This review focuses on the chemical and biological aspects of small molecule TPO agonists described to date.


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Sensing Reactive Oxygen and Nitrogen Species Using Selective Fluorescent Probes
Nobuaki Soh and Toshihiko Imato

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generally thought to be important mediators of various pathological conditions. Since fluorescent probes are promising tools for clarifying the functions of biomolecules in biological systems as demonstrated by the case of Ca²⁺ fluorescent probes, interest in the use of fluorescent probes for sensing ROS/RNS is increasing. Although fluorescent probes such as 2’,7’-dichlorodihydrofluorescein (DCFH) and dihydrorhodamine 123 (DHR123) have traditionally been used for sensing ROS/RNS, many reports suggest that such probes are not suitable for sensing specific ROS/RNS individually but for whole oxidative stresses caused by ROS/RNS due to their lack of selectivity for ROS/RNS. However, it is quite important to detect specific ROS/RNS with a high selectively because each ROS/RNS has its own physiological activities and has unique characteristic roles. To achieve such specificity, novel functional fluorescent probes that can distinguish specific ROS/RNS individually with high selectivity, have been developed in recent years. The purpose of this review is to highlight recent advances in the design and development of such selective ROS/RNS fluorescent probes that should have a great potential for evaluating the unique roles of individual ROS/RNS in biological processes.


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Interferons: Mechanisms, Biological Activities and Survey of their Use in Human Diseases
Dalia Obeid and Brigitte Bauvois

Human interferons (IFNs) form a family of cytokines produced by a large number of cells. On the basis of their physicochemical and biological properties, the IFN family can be subdivided into two subtypes: the Type I IFNs (α, β, ω) and the Type II IFN represented by IFN-γ. IFN binding to specific cell surface receptors activates the Jaks kinases which phosphorylate Stats leading to their dimerization, translocation to the nucleus, and activation of their transcription factor activity. In addition, IFNs activate several protein kinases including the MAP kinase family, and downstream transcription factors through Stat-independent pathways. IFNs could induce the expression of more than 300 genes. Through these Stat-dependent and Stat-independent pathways, IFNs exhibit antiviral, antitumor, and immune-enhancing properties. Recombinant DNA technology has allowed IFNs to be produced in sufficient quantity for large scale clinical studies. IFNs are effective in the treatment of viral diseases (hepatitis B and C, VIH, HPV), solid tumors (melanoma, Kaposi’s sarcoma, renal and hepatocellular carcinomas), hematological disorders (hairy cell leukemia, multiple myeloma, chronic granulomatosis) and in other diseases such as multiple sclerosis and infancy hemangioma. The limitations to their clinical use include side effects such as induced toxicity and development of antibodies in patients. Pegylated IFNs (IFN covalently bound to polyethylene glycol polymers) with little inmunogenicity, longer plasma half–life, greater stability and efficacy, as single agents or in combination with other therapeutic agents, appear to improve IFN clinical efficacy. New options involve IFN gene therapy.


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Preparation and Oxidation Chemistry of the Catechol Estrogens: Relevance to Estrogen-Related Carcinogenesis and Potential for Drug Design
Alessandro Pezzella, Liliana Lista, Alessandra Napolitano and Marco d’Ischia

In this review we will briefly survey the oxidation chemistry of the catechol estrogens (2-hydroxy- and 4-hydroxyestradiol, 2-OH-E and 4-OH-E) as a result of the research carried out in the authors’ laboratory and other centers during the past decade. The central focus of the paper will be on the main pathways of oxidative modification and their possible relevance to the mechanisms of estrogen-related carcinogenesis. The chemical bases underlying the different reactivity and toxicity of 2-hydroxy and 4-hydroxyestradiol will be addressed. The value of catechol estrogen oxidation in the discovery of novel functionalized or modified steroidal scaffolds of potential pharmaceutical interest will be also briefly highlighted.