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Synthesis and structure-activity relationship of furoquinolinediones as inhibitors of Tyrosyl-DNA phosphodiesterase 2 (TDP2). 2018
Le-Mao Yu, and
Zhu Hu, and
Yu Chen, and
Azhar Ravji, and
Sophia Lopez, and
Caroline B Plescia, and
Qian Yu, and
Hui Yang, and
Monica Abdelmalak, and
Sourav Saha, and
Keli Agama, and
Evgeny Kiselev, and
Christophe Marchand, and
Yves Pommier, and
Lin-Kun An
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
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.
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