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

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April 11, 2013
• 年：2013
• 卷：56
• 期：7
• 页码：2885-2903
• 全文大小：847K
• 年卷期：v.56,no.7(April 11, 2013)
• ISSN：1520-4804

文摘

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.