Transition Metal Ions Promote the Bioavailability of Hydrophobic Therapeutics: Cu and Zn Interactions with RNA Polymerase I Inhibitor CX5461

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 chemothera...

Full description

Saved in:
Bibliographic Details
Published inChemistry : a European journal Vol. 24; no. 24; pp. 6334 - 6338
Main Authors Prosser, Kathleen E., Leung, Ada W. Y., Harrypersad, Shane, Lewis, Andrew R., Bally, Marcel B., Walsby, Charles J.
Format Journal Article
LanguageEnglish
Published Germany Wiley Subscription Services, Inc 25.04.2018
Subjects
Bioavailability
bioinorganic
cancer
Chemistry
Computer applications
Copper
Cytotoxicity
DNA-directed RNA polymerase
Drug development
Hydrophobicity
Metal ions
nuclear magnetic resonance
pH effects
Pyrazine
Ribonucleic acid
RNA
Solubilization
Toxicity
Zinc
bioinorganic
copper
cancer
nuclear magnetic resonance
zinc
Online AccessGet full text

Cover

More Information
Summary: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 Cu2+ or Zn2+ 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. 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.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201800289