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Ruthenium polypyridyl complexes and their modes of interaction with DNA: Is there a correlation between these interactions and the antitumor activity of the compounds?

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      Abstract

      Various interaction modes between a group of six ruthenium polypyridyl complexes and DNA have been studied using a number of spectroscopic techniques. Five mononuclear species were selected with formula [Ru(tpy)L 1L 2] (2− n)+ , and one closely related dinuclear cation of formula [{Ru(apy)(tpy)} 2{μ-H 2N(CH 2) 6NH 2}] 4+. The ligand tpy is 2,2′:6′,2″-terpyridine and the ligand L 1 is a bidentate ligand, namely, apy (2,2′-azobispyridine), 2-phenylazopyridine, or 2-phenylpyridinylmethylene amine. The ligand L 2 is a labile monodentate ligand, being Cl , H 2O, or CH 3CN. All six species containing a labile L 2 were found to be able to coordinate to the DNA model base 9-ethylguanine by 1H NMR and mass spectrometry. The dinuclear cationic species, which has no positions available for coordination to a DNA base, was studied for comparison purposes. The interactions between a selection of four representative complexes and calf-thymus DNA were studied by circular and linear dichroism. To explore a possible relation between DNA-binding ability and toxicity, all compounds were screened for anticancer activity in a variety of cancer cell lines, showing in some cases an activity which is comparable to that of cisplatin. Comparison of the details of the compound structures, their DNA binding, and their toxicity allows the exploration of structure–activity relationships that might be used to guide optimization of the activity of agents of this class of compounds.

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      The online version of this article (doi:10.1007/s00775-008-0460-x) contains supplementary material, which is available to authorized users.

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      Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays

      A tetrazolium salt has been used to develop a quantitative colorimetric assay for mammalian cell survival and proliferation. The assay detects living, but not dead cells and the signal generated is dependent on the degree of activation of the cells. This method can therefore be used to measure cytotoxicity, proliferation or activation. The results can be read on a multiwell scanning spectrophotometer (ELISA reader) and show a high degree of precision. No washing steps are used in the assay. The main advantages of the colorimetric assay are its rapidity and precision, and the lack of any radioisotope. We have used the assay to measure proliferative lymphokines, mitogen stimulations and complement-mediated lysis.
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        How to study proteins by circular dichroism.

        Circular dichroism (CD) is being increasingly recognised as a valuable technique for examining the structure of proteins in solution. However, the value of many studies using CD is compromised either by inappropriate experimental design or by lack of attention to key aspects of instrument calibration or sample characterisation. In this article, we summarise the basis of the CD approach and its application to the study of proteins, and then present clear guidelines on how reliable data can be obtained and analysed.
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          Feasibility of drug screening with panels of human tumor cell lines using a microculture tetrazolium assay.

          For the past 30 years strategies for the preclinical discovery and development of potential anticancer agents have been based largely upon the testing of agents in mice bearing transplantable leukemias and solid tumors derived from a limited number of murine as well as human sources. The feasibility of implementing an alternate approach, namely combined in vitro/in vivo screening for selective cytotoxicity among panels of human tumor cell lines derived from a broad spectrum of human solid tumors is under investigation. A group of 30 cell lines acquired from a variety of sources and representing 8 lung cancer pathologies as well as 76 cell lines representing 10 other categories of human cancer (carcinomas of colon, breast, kidney, prostate, ovary, head and neck; glioma; leukemia; melanoma; and sarcoma) have exhibited acceptable growth characteristics and suitable colorimetric profiles in a single, standard culture medium. Measurements of in vitro growth in microculture wells by cell-mediated reduction of tetrazolium showed excellent correlation (0.89 less than r2 less than 0.98) with measurements of cellular protein in adherent cell line cultures as well as viable cell count in suspension cell line cultures (0.94 less than r2 less than 0.99). Since the microculture tetrazolium assay provides sensitive and reproducible indices of growth as well as drug sensitivity in individual cell lines over the course of multiple passages and several months' cultivation, it appears suitable for initial-stage in vitro drug screening.
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            Author and article information

            Affiliations
            [1 ]Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands
            [2 ]School of Chemistry, University of Birmingham, Edgbaston, Birmingham, B15 2TT UK
            [3 ]Department of Chemistry, University of Warwick, Coventry, CV4 7AL UK
            Contributors
            +44-121-4147871 , m.j.hannon@bham.ac.uk
            +31-71-5274671 , reedijk@chem.leidenuniv.nl
            Journal
            J Biol Inorg Chem
            Journal of Biological Inorganic Chemistry
            Springer-Verlag (Berlin/Heidelberg )
            0949-8257
            1432-1327
            16 December 2008
            16 December 2008
            March 2009
            : 14
            : 3
            : 439-448
            3036821
            19085018
            460
            10.1007/s00775-008-0460-x
            © The Author(s) 2008
            Categories
            Original Paper
            Custom metadata
            © SBIC 2009

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