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Transition Metal Ions Promote the Bioavailability of Hydrophobic Therapeutics: Cu and Zn Interactions with RNA Polymerase I Inhibitor CX5461
Author(s) -
Prosser Kathleen E.,
Leung Ada W. Y.,
Harrypersad Shane,
Lewis Andrew R.,
Bally Marcel B.,
Walsby Charles J.
Publication year - 2018
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201800289
Subject(s) - bioavailability , chemistry , denticity , cytotoxicity , pyrazine , solubility , transition metal , aqueous solution , molecule , drug , metal ions in aqueous solution , combinatorial chemistry , coordination complex , solubilization , biophysics , metal , inorganic chemistry , stereochemistry , biochemistry , in vitro , organic chemistry , pharmacology , biology , catalysis
Low aqueous solubility is a major barrier to the clinical application of otherwise promising drug candidates. We demonstrate that this issue can be resolved in medicinal molecules containing potential ligating groups, through the addition of labile transition‐metal ions. Incubation of the chemotherapeutic CX5461 with Cu 2+ or Zn 2+ enables solubilization at neutral pH but does not affect intrinsic cytotoxicity. Spectroscopic and computational studies demonstrate that this arises from coordination to the pyrazine functionality of CX5461 and may involve bidentate coordination at physiological pH.