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    Water-soluble bis(1,10-phenanthroline) octanedioate Cu2+ and Mn2+ complexes with unprecedented nano and picomolar in vitro cytotoxicity: promising leads for chemotherapeutic drug development


    Kellet, Andrew and O'Connor, Mark and McCann, Malachy and Howe, Orla and Casey, Alan and McCarron, Pauraic and Kavanagh, Kevin and McNamara, Mary and Kennedy, Sean and May, Donald D. and Skell, Philip S. and O'Shea, Denis and Devereux, Michael (2011) Water-soluble bis(1,10-phenanthroline) octanedioate Cu2+ and Mn2+ complexes with unprecedented nano and picomolar in vitro cytotoxicity: promising leads for chemotherapeutic drug development. MedChemComm, 2 (7). pp. 579-584. ISSN 2040-2503

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    Abstract

    Dinuclear Cu2+ and Mn2+ bis-phenanthroline octanedioate compounds exhibit rapid, unprecedented nano and picomolar in vitro cytotoxicity against human-derived colorectal cancer lines (HT29, SW480 and SW620) and are less cytotoxic toward non-cancerous normal human keratinocyte cells (HaCaT). Both complexes displayed greater in vivo drug tolerance compared to cisplatin when examined using the insect Galleria mellonella. The compounds are potent generators of intracellular reactive oxygen species within HT29 cells, display avid DNA binding and induce O2-dependent cleavage of supercoiled pUC18 DNA. The Cu2+ complex was found to display self-cleaving nuclease activity and a mechanism of deoxyribose C–H bond activation is proposed, based on interactions with the superoxide anion and hydrogen peroxide along with DNA cleavage observations under anaerobic conditions and with an excess of the metal chelator EDTA.

    Item Type: Article
    Additional Information: The definitive version of this article is available at DOI: 10.1039/c0md00266f . This paper is dedicated to the memory of Prof. Philip S. Skell (1918–2010), member, United States National Academy of Sciences. DDM would like to thank PSS for ‘‘teaching me that the best scientists have a broad base of knowledge in their field and open and curious minds in their exploration of nature’s secrets’’. The authors wish to acknowledge financial support from the Dublin Institute of Technology Capacity Building Scheme for Strategic Research progamme (CaBS). This work has been carried out (in part) within the structures of the Focas Research Institute, DIT, funded under The Irish National Development Plan with assistance from the European Regional Development Fund.
    Keywords: Water-soluble bis; octanedioate Cu2+ and Mn2+ complexes; in vitro cytotoxicity; human-derived colorectal cancer lines; chemotherapeutic drug development;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 4083
    Depositing User: Dr. Kevin Kavanagh
    Date Deposited: 16 Jan 2013 16:28
    Journal or Publication Title: MedChemComm
    Publisher: Royal Society of Chemistry
    Refereed: Yes
    URI:

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