Transition Metal Ions Promote the Bioavailability of Hydrophobic Therapeutics: Cu and Zn Interactions with RNA Polymerase I Inhibitor CX5461. Issue 24 (6th April 2018)

• Record Type: Journal Article
• Authors: Prosser, Kathleen E.; Leung, Ada W. Y.; Harrypersad, Shane; Lewis, Andrew R.; Bally, Marcel B.; Walsby, Charles J.
• Is Part Of: Chemistry. Volume 24:Issue 24(2018)
• Page Start: 6334
• Page End: 6338
• Publication Date: 2018-04-06
• Subjects: bioinorganic -- cancer -- copper -- nuclear magnetic resonance -- zinc; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201800289
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: 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. Abstract : Overcoming insolubility : A new method for solubilizing a hydrophobic drug while maintaining its intrinsic activity is demonstrated, using transition‐metal–ion interactions with ligating functional groups.