Synthesis and structure-activity relationship of furoquinolinediones as inhibitors of Tyrosyl-DNA phosphodiesterase 2 (TDP2)

• Published in: European journal of medicinal chemistry 2018-05, Vol.151, p.777-796
• Main Authors: Yu, Le-Mao, Hu, Zhu, Chen, Yu, Ravji, Azhar, Lopez, Sophia, Plescia, Caroline B., Yu, Qian, Yang, Hui, Abdelmalak, Monica, Saha, Sourav, Agama, Keli, Kiselev, Evgeny, Marchand, Christophe, Pommier, Yves, An, Lin-Kun
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Chickens; DNA repair; Furoquinolinedione; Humans; Inhibitor; Molecular Docking Simulation; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - metabolism; Phosphodiesterase Inhibitors - chemical synthesis; Phosphodiesterase Inhibitors - chemistry; Phosphodiesterase Inhibitors - pharmacology; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; Recombinant Proteins - metabolism; Structure-Activity Relationship; Topoisomerase; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Tyrosyl-DNA phosphodiesterase
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.04.024

Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a recently discovered enzyme specifically repairing topoisomerase II (TOP2)-mediated DNA damage. It has been shown that inhibition of TDP2 synergize with TOP2 inhibitors. Herein, we report the discovery of the furoquinolinedione chemotype as a suitable skeleton for the development of selective TDP2 inhibitors. Compound 1 was identified as a TDP2 inhibitor as a result of screening our in-house compound library for compounds selective for TDP2 vs. TDP1. Further SAR studies provide several selective TDP2 inhibitors at low-micromolar range. The most potent compound 74 shows inhibitory activity with IC50 of 1.9 and 2.1 μM against recombinant TDP2 and TDP2 in whole cell extracts (WCE), respectively. [Display omitted] •A novel TDP2 hit (1) was found through screening from in-house chemical library.•Seventy seven furoquinolinedione analogues were synthesized.•Compound 74 showed the most TDP2 inhibition with IC50 at low micromolar range.•The SAR was analyzed.•Furoquinolinedinone chemotype represents a novel skeleton for novel TDP2 inhibitors.