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      Organometallic 3-(1 H-Benzimidazol-2-yl)-1 H-pyrazolo[3,4- b]pyridines as Potential Anticancer Agents

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          Abstract

          Six organometallic complexes of the general formula [M IICl(η 6- p-cymene)(L)]Cl, where M = Ru ( 11a, 12a, 13a) or Os ( 11b, 12b, 13b) and L = 3-(1 H-benzimidazol-2-yl)-1 H-pyrazolo[3,4- b]pyridines ( L1L3) have been synthesized. The latter are known as potential cyclin-dependent kinase (Cdk) inhibitors. All compounds have been comprehensively characterized by elemental analysis, one- and two-dimensional NMR spectroscopy, UV–vis spectroscopy, ESI mass spectrometry, and X-ray crystallography ( 11b and 12b). The multistep synthesis of 3-(1 H-benzimidazol-2-yl)-1 H-pyrazolo[3,4- b]pyridines ( L1L3), which was reported by other researchers, has been modified by us essentially (e.g., the synthesis of 5-bromo-1 H-pyrazolo[3,4- b]pyridine-3-carboxylic acid ( 3) via 5-bromo-3-methyl-1 H-pyrazolo[3,4- b]pyridine ( 2); the synthesis of 1-methoxymethyl-2,3-diaminobenzene ( 5) by avoiding the use of unstable 2,3-diaminobenzyl alcohol; and the activation of 1 H-pyrazolo[3,4- b]pyridine-3-carboxylic acids ( 1, 3) through the use of an inexpensive coupling reagent, N, N′-carbonyldiimidazole (CDI)). Stabilization of the 7b tautomer of methoxymethyl-substituted L3 by coordination to a metal(II) center, as well as the NMR spectroscopic characterization of two tautomers 7b- L3 and 4b′- L3 in a metal-free state are described. Structure–activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells, as well as Cdk inhibitory activity, are also reported.

          Abstract

          Three organic compounds L1−L3, known as potential Cdk inhibitors, and six novel complexes of the general formula [M IICl(η 6- p-cymene)(L)]Cl, where M = Ru ( 11a, 12a, 13a) or Os ( 11b, 12b, 13b) and L = L1−L3, correspondingly, have been synthesized and comprehensively characterized by elemental analysis, ESI mass-spectrometry, spectroscopic and X-ray diffraction methods. Structure−activity relationships, with regard to cytotoxicity and cell cycle effects, in human cancer cells, as well as Cdk inhibitory activity, are reported.

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          Bioorganometallic chemistry--from teaching paradigms to medicinal applications.

          In undergraduate level organometallic chemistry courses students are usually taught that organometallic compounds are toxic and unstable in air and water. While this is true of many complexes, some are also non-toxic and stable in air and water. Indeed, bioorganometallic chemistry, the study of biomolecules or biologically active molecules that contain at least one carbon directly bound to a metal, is a thriving subject, and air and water stability is a general pre-requisite. This interdisciplinary field is located at the borderline between chemistry, biochemistry, biology and medicine. In this tutorial review, various aspects of bioorganometallic chemistry are introduced, with the main emphasis on medicinal organometallic compounds. Organometallic therapeutics for cancer, HIV and malaria and other medicinal applications are described. It is also shown how rational ligand design has led to new improved therapies much in the same way that an organometallic chemist working in catalysis will design new ligands for improved activities.
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            Medicinal organometallic chemistry: designing metal arene complexes as anticancer agents.

            The field of medicinal inorganic chemistry is rapidly advancing. In particular organometallic complexes have much potential as therapeutic and diagnostic agents. The carbon-bound and other ligands allow the thermodynamic and kinetic reactivity of the metal ion to be controlled and also provide a scaffold for functionalization. The establishment of structure-activity relationships and elucidation of the speciation of complexes under conditions relevant to drug testing and formulation are crucial for the further development of promising medicinal applications of organometallic complexes. Specific examples involving the design of ruthenium and osmium arene complexes as anticancer agents are discussed.
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              CDK inhibitors in cancer therapy: what is next?

              The pursuit for drugs that inhibit cyclin-dependent kinases (CDKs) has been an intense area of research for more than 15 years. The first-generation inhibitors, Flavopiridol and CY-202, are in late-stage clinical trials, but so far have demonstrated only modest activity. Several second-generation inhibitors are now in clinical trials. Future approaches to determine clinical benefit need to incorporate both the lessons learned from these early compounds and information recently obtained from the genetic analysis of CDKs in preclinical models. Here we discuss key concepts that should be considered when validating the clinical utility of CDK inhibitors in cancer therapy.
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                Author and article information

                Journal
                Inorg Chem
                ic
                inocaj
                Inorganic Chemistry
                American Chemical Society
                0020-1669
                1520-510X
                27 October 2011
                21 November 2011
                : 50
                : 22
                : 11715-11728
                Affiliations
                [1]University of Vienna, Institute of Inorganic Chemistry, Währinger Strasse 42, A-1090 Vienna, Austria
                Author notes
                Article
                10.1021/ic201704u
                3255473
                22032295
                e6513395-9fb8-425e-97ae-ff36cd4a22c7
                Copyright © 2011 American Chemical Society

                This is an open-access article distributed under the ACS AuthorChoice Terms & Conditions. Any use of this article, must conform to the terms of that license which are available at http://pubs.acs.org.

                History
                : 05 August 2011
                : 27 October 2011
                : 21 November 2011
                Categories
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                Custom metadata
                ic201704u
                ic-2011-01704u

                Inorganic & Bioinorganic chemistry
                Inorganic & Bioinorganic chemistry

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