A Platinum(II) Phenylphenanthroimidazole with an Extended Side‐Chain Exhibits Slow Dissociation from a c‐Kit G‐Quadruplex Motif. Issue 52 (18th November 2013)

• Record Type: Journal Article
• Authors: Castor, Katherine J.; Liu, Zhaomin; Fakhoury, Johans; Hancock, Mark A.; Mittermaier, Anthony; Moitessier, Nicolas; Sleiman, Hanadi F.
• Is Part Of: Chemistry. Volume 19:Issue 52(2013)
• Page Start: 17836
• Page End: 17845
• Publication Date: 2013-11-18
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201301590
• Languages: English
• ISSNs: 0947-6539

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>A series of three platinum(II) phenanthroimidazoles each containing a protonable side‐chain appended from the phenyl moiety through copper(I)‐catalyzed azide–alkyne cycloaddition (CuAAC) were evaluated for their capacities to bind to human telomere, <italic>c‐Myc</italic>, and <italic>c‐Kit</italic> derived G‐quadruplexes. The side‐chain has been optimized to enable a multivalent binding mode to G‐quadruplex motifs, which would potentially result in selective targeting. Molecular modeling, high‐throughput fluorescence intercalator displacement (HT‐FID) assays, and surface plasmon resonance (SPR) studies demonstrate that complex <bold>2</bold> exhibits significantly slower dissociation rates compared to platinum phenanthroimidazoles without side‐chains and other reported G‐quadruplex binders. Complex <bold>2</bold> showed little cytotoxicity in HeLa and A172 cancer cell lines, consistent with the fact that it does not follow a telomere‐targeting pathway. Preliminary mRNA analysis shows that <bold>2</bold> specifically interacts with the ckit promoter region. Overall, this study validates <bold>2</bold> as a useful molecular probe for <italic>c‐Kit</italic> related cancer pathways.</p> </abstract>