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    Detailed Biological Profiling of a Photoactivated and Apoptosis Inducing pdppz Ruthenium(II) Polypyridyl Complex in Cancer Cells


    Cloonan, Suzanne M. and Elmes, Robert B.P. and Erby, Marialuisa and Bright, Sandra A. and Poynton, Fergus E. and Nolan, Derek E. and Quinn, Susan J. and Gunnlaugsson, Thorfinnur and Williams, D. Clive (2015) Detailed Biological Profiling of a Photoactivated and Apoptosis Inducing pdppz Ruthenium(II) Polypyridyl Complex in Cancer Cells. Journal of Medicinal Chemistry, 58 (11). pp. 4494-4505. ISSN 0022-2623

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    Abstract

    Ruthenium polypyridyl complexes show great promise as new photodynamic therapy (PDT) agents. However, a lack of detailed understanding of their mode of action in cells poses a challenge to their development. We have designed a new Ru(II) PDT candidate that efficiently enters cells by incorporation of the lipophilic aromatic pdppz ([2,3-h]dipyrido[3,2-a:2′,3′-c]phenazine) ligand and exhibits photoactivity through incorporation of 1,4,5,8-tetraazaphenanthrene ancillary ligands. Its photoreactivity toward biomolecules was studied in vitro, where light activation caused DNA cleavage. Cellular internalization occurred via an energy dependent mechanism. Confocal and transmission electron microscopy revealed that the complex localizes in various organelles, including the mitochondria. The complex is nontoxic in the dark, with cellular clearance within 96 h; however, upon visible light activation it induces caspase-dependent and reactive-oxygen-species-dependent apoptosis, with low micromolar IC50 values. This investigation greatly increases our understanding of such systems in cellulo, aiding development and realization of their application in cancer therapy.

    Item Type: Article
    Keywords: Ligands; Genetics; Cells; Light Toxicity;
    Academic Unit: Faculty of Science and Engineering > Chemistry
    Item ID: 12534
    Identification Number: https://doi.org/10.1021/acs.jmedchem.5b00451
    Depositing User: Robert Elmes
    Date Deposited: 06 Mar 2020 16:59
    Journal or Publication Title: Journal of Medicinal Chemistry
    Publisher: ACS Publications
    Refereed: Yes
    URI:

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