title: Design, synthesis, and biological evaluation of a series of benzo[de][1,7]naphthyridin-7(8H)-ones bearing a functionalized longer chain appendage as novel PARP1 inhibitors.
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 H2O2-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.
authors.affiliation: CAS Key Laboratory of Receptor Research, and Synthetic Organic & Medicinal Chemistry Laboratory, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Na
authors.initials: N
authors.lastname: Ye
authors.forename: Chuan-Huizi
authors.initials: CH
authors.lastname: Chen
authors.forename: Tiantian
authors.initials: T
authors.lastname: Chen
authors.forename: Zilan
authors.initials: Z
authors.lastname: Song
authors.forename: Jin-Xue
authors.initials: JX
authors.lastname: He
authors.forename: Xia-Juan
authors.initials: XJ
authors.lastname: Huan
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Song
authors.forename: Qiufeng
authors.initials: Q
authors.lastname: Liu
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Jian
authors.initials: J
authors.lastname: Ding
authors.forename: Yechun
authors.initials: Y
authors.lastname: Xu
authors.forename: Ze-Hong
authors.initials: ZH
authors.lastname: Miao
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020128:Inhibitory Concentration 50; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009287:Naphthyridines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1