Asymmetrically Substituted Quadruplex-Binding Naphthalene Diimide Showing Potent Activity in Pancreatic Cancer Models.

Abstract

Targeting of genomic quadruplexes is an approach to treating complex human cancers. We describe a series of tetra-substituted naphthalene diimide (ND) derivatives with a phenyl substituent directly attached to the ND core. The lead compound (SOP1812) has 10 times superior cellular and in vivo activity compared with previous ND compounds and nanomolar binding to human quadruplexes. The pharmacological properties of SOP1812 indicate good bioavailability, which is consistent with the in vivo activity in xenograft and genetic models for pancreatic cancer. Transcriptome analysis shows that it down-regulates several cancer gene pathways, including Wnt/β-catenin signaling.

• Authors: Ahmed A Ahmed, Richard Angell, Sally Oxenford, Jenny Worthington, Nicole Williams, Naomi Barton, Thomas G Fowler, Daniel E O'Flynn, Mihiro Sunose, Matthew McConville, Tam Vo, W David Wilson, Saadia A Karim, Jennifer P Morton, Stephen Neidle
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 11 Issue 8 Pg. 1634-1644 (Aug 13 2020) ISSN: 1948-5875 [Print] United States
• PMID: 32832034 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 American Chemical Society.