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
Kellett A., O'Connor M., McCann M., Howe O., Casey A., McCarron P., McNamara M., Kennedy S., May D.D., Skell P.S., O'Shea D., Devereux M.
Medicinal Chemical Communications, 2 (7), 569-676, 2011.
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.
Highlight: Journal front cover, Volume 2, July 2011.