Senaweera Sameera, He Tianyu, Cui Haixi, Aihara Hideki, Wang Zhengqiang
Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, United States.
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, United States.
Med Chem Res. 2021 Feb;30(2):371-386. doi: 10.1007/s00044-020-02662-w. Epub 2020 Nov 19.
Tyrosyl-DNA phosphodiesterase 2 (TDP2) repairs topoisomerase II (Top2) mediated DNA damages, including double-strand breaks (DSBs) that underpin the anticancer mechanism of clinical TOP2 poisons such as etoposide (ETP). Inhibition of TDP2 could sensitize cancer cells toward TOP2 poisons by increasing Top2 cleavage complex. We have previously identified isoquinoline-1,3-dione as a selective inhibitor type of TDP2. However, the reported structure-activity relationship (SAR) was limited to simple substitutions on the isoquinoline-1,3-dione core. Herein, we report the extended SAR consisting of the synthesis and testing of a total of 50 analogs featuring N-2 and C-4 modifications. Major SAR observations include the loss of potency upon N-2 substitution, the lack of inhibition with C-4 enamine analogs (subtype ), or any other C-4 modifications (subtypes ) except for the benzylidene substitution (subtype ), where eight analogs showed low micromolar potency. The best analog, , inhibited TDP2 with an IC of 4.8 μM. Molecular modeling was performed to help understand the observed SAR trends. Overall, these SAR observations which could significantly benefit future work on the design of improved TDP2 inhibitors.
酪氨酰-DNA磷酸二酯酶2（TDP2）修复拓扑异构酶II（Top2）介导的DNA损伤，包括双链断裂（DSB），而双链断裂是依托泊苷（ETP）等临床TOP2毒素抗癌机制的基础。抑制TDP2可通过增加Top2切割复合物使癌细胞对TOP2毒素敏感。我们之前已鉴定异喹啉-1,3-二酮为TDP2的一种选择性抑制剂类型。然而，所报道的构效关系（SAR）仅限于异喹啉-1,3-二酮核心上的简单取代。在此，我们报道了扩展的构效关系，包括总共50个具有N-2和C-4修饰的类似物的合成与测试。主要的构效关系观察结果包括N-2取代后活性丧失、C-4烯胺类似物（亚型）无抑制作用，以及除亚苄基取代（亚型）外的任何其他C-4修饰（亚型）均无抑制作用，其中八个类似物表现出低微摩尔活性。最佳类似物 抑制TDP2的IC为4.8 μM。进行了分子建模以帮助理解观察到的构效关系趋势。总体而言，这些构效关系观察结果可为未来改进TDP2抑制剂设计的工作带来显著益处。
