School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
Eur J Med Chem. 2022 Aug 5;238:114445. doi: 10.1016/j.ejmech.2022.114445. Epub 2022 May 10.
As a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 2 (TDP2) can specifically repair topoisomerase 2 (TOP2)-mediated DNA damage, resulting in cancer cell resistance to TOP2 inhibitors. Its inhibitors can enhance the anticancer efficacy of TOP2 inhibitors. In this work, we report the discovery of natural product myrtucommulone E as selective TDP2 inhibitor and its first enantioselective total synthesis through a pivotal CPA-catalyzed Michael addition reaction. A series of myrtucommulone E analogues were asymmetrically synthesized and evaluated for TDP2 and TDP1 inhibitions, and cytotoxicity. Analogue (+)-29 shows good TDP2 inhibition potency (5.4 ± 0.25 μM), but no TDP1 inhibition at 100 μM concentration, and can significantly enhance the cytotoxicity of TOP2 inhibitor etoposide in both DU145 (CI = 0.26) and DT40 hTDP2 cells (CI = 0.48).
作为一种最近发现的 DNA 修复酶，酪氨酸-DNA 磷酸二酯酶 2（TDP2）可以特异性修复拓扑异构酶 2（TOP2）介导的 DNA 损伤，导致癌细胞对 TOP2 抑制剂产生耐药性。其抑制剂可以增强 TOP2 抑制剂的抗癌疗效。在这项工作中，我们报告了天然产物桃金娘烯醇 E 作为选择性 TDP2 抑制剂的发现及其通过关键的 CPA 催化的迈克尔加成反应的首次对映选择性全合成。通过不对称合成了一系列桃金娘烯醇 E 类似物，并对 TDP2 和 TDP1 的抑制作用和细胞毒性进行了评价。类似物 (+)-29 表现出良好的 TDP2 抑制活性（5.4 ± 0.25 μM），但在 100 μM 浓度下对 TDP1 没有抑制作用，并且可以在 DU145（CI = 0.26）和 DT40 hTDP2 细胞中显著增强 TOP2 抑制剂依托泊苷的细胞毒性（CI = 0.48）。
