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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.

SUBMITTER: Ahmed AA

PROVIDER: S-EPMC7429975 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Ahmed Ahmed A AA Angell Richard R Oxenford Sally S Worthington Jenny J Williams Nicole N Barton Naomi N Fowler Thomas G TG O'Flynn Daniel E DE Sunose Mihiro M McConville Matthew M Vo Tam T Wilson W David WD Karim Saadia A SA Morton Jennifer P JP Neidle Stephen S

ACS medicinal chemistry letters 20200716 8

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 <i>in vivo</i> 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 <i>in v ...[more]

PMID: 32832034

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