2. Academic Validation
  3. Discovery, enantioselective synthesis of myrtucommulone E analogues as tyrosyl-DNA phosphodiesterase 2 inhibitors and their biological activities

Discovery, enantioselective synthesis of myrtucommulone E analogues as tyrosyl-DNA phosphodiesterase 2 inhibitors and their biological activities

  • Eur J Med Chem. 2022 Aug 5:238:114445. doi: 10.1016/j.ejmech.2022.114445.
Yu Zhang 1,  Hao Yang 1,  Fang-Ting Wang 1,  Xing Peng 1,  Hai-Yang Liu 2,  Qing-Jiang Li 3,  Lin-Kun An 4
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 2 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.
  • 3 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. Electronic address: liqingj3@mail.sysu.edu.cn.
  • 4 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China; Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangzhou, 510006, China. Electronic address: lssalk@mail.sysu.edu.cn.
PMID: 35580424 DOI: 10.1016/j.ejmech.2022.114445
Abstract

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).

Keywords

Anticancer; DNA damage; Inhibitor; Myrtucommulone; Synergy; Topoisomerase; Tyrosyl-DNA phosphodiesterase.

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