Design, synthesis, and biological evaluation of a series of benzo[ de ][1,7]naphthyridin-7(8 H)-ones bearing a functionalized longer chain appendage as novel PARP1 inhibitors

Na Ye, Chuan Huizi Chen, Tiantian Chen, Zilan Song, Jin Xue He, Xia Juan Huan, Shan Shan Song, Qiufeng Liu, Yi Chen, Jian Ding, Yechun Xu, Ze Hong Miao, Ao Zhang

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

A series of benzo[de][1,7]naphthyridin-7(8H)-ones possessing a functionalized long-chain appendage have been designed and evaluated as novel PARP1 inhibitors. The initial effort led to the first-generation PARP1 inhibitor 26 bearing a terminal phthalazin-1(2H)-one framework and showing remarkably high PARP1 inhibitory activity (0.31 nM) but only moderate potency in the cell. Further effort generated the second-generation lead 41, showing high potency against both the PARP1 enzyme and BRCA-deficient cells, especially for the BRCA1-deficient MDA-MB-436 cells (CC50 < 0.26 nM). Mechanistic studies revealed that the new PARP1 inhibitors significantly inhibited H 2O2-triggered PARylation in SKOV3 cells, induced cellular accumulation of DNA double-strand breaks, and impaired cell-cycle progression in BRCA2-deficient cells. Significant potentiation on the cytotoxicity of Temozolomide was also observed. The unique structural character and exceptionally high potency of 41 made it stand out as a promising drug candidate worthy for further evaluation.

Original languageEnglish (US)
Pages (from-to)2885-2903
Number of pages19
JournalJournal of Medicinal Chemistry
Volume56
Issue number7
DOIs
StatePublished - Apr 11 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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