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  3. 20-Deoxyingenol ester and ether derivatives: Synthesis, properties and cytotoxicity

20-Deoxyingenol ester and ether derivatives: Synthesis, properties and cytotoxicity

  • Bioorg Chem. 2025 Mar:156:108207. doi: 10.1016/j.bioorg.2025.108207.
Zijian Liu 1,  Yaxu Wang 2,  Qingning Jiao 3,  Yan Liu 1,  Shuai Shen 1,  Hongwei Zhao 4,  Ziang Gao 1,  Guo-Dong Yao 1,  Liwei Gu 5,  Qingbo Liu 6,  Shao-Jiang Song 7
Affiliations

Affiliations

  • 1 Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China.
  • 2 Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
  • 3 Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China; Jilin Yizheng Pharmaceutical Group Co., Ltd., Jilin Province, Siping 136001, China.
  • 4 Jilin Yizheng Pharmaceutical Group Co., Ltd., Jilin Province, Siping 136001, China.
  • 5 State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China. Electronic address: lwgu@icmm.ac.cn.
  • 6 Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China; Jilin Yizheng Pharmaceutical Group Co., Ltd., Jilin Province, Siping 136001, China. Electronic address: liuqingbolily@163.com.
  • 7 Key Laboratory of Computational Chemistry-Based Natural Antitumor Drug Research & Development, Liaoning Province, Engineering Research Center of Natural Medicine Active Molecule Research & Development, Liaoning Province Key Laboratory of Natural Bioactive Compounds Discovery & Modification, Shenyang, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China. Electronic address: songsj99@163.com.
PMID: 39864376 DOI: 10.1016/j.bioorg.2025.108207
Abstract

The C-3 and C-5 substituted 20-deoxyingenol monoesters are important active components in Euphorbiaceae plants. Nonetheless, their similar physical properties make them difficult to distinguish. The present study developed fast and efficient rules for identifying the esterification sites of 20-deoxyingenol based on a series of chemical syntheses of monoesters and literature research, utilizing NMR spectroscopy, optical rotation analysis, and chromatographic retention behavior. In addition, a series of 20-deoxyingenol ether derivatives, including 1,3,4-oxadiazole derivatives, were synthesized. The cytotoxic activities of 20-deoxyingenol derivatives were evaluated on A549 and HepG2 cell lines. Notably, 20-deoxyingenol 1,3,4-oxadiazole derivative 22 (IC50 = 8.8 μM) exhibited significant Anticancer activity against HepG2 cells with low toxicity to normal cells (IC50 > 50 μM), making it a promising compound. We investigated the potential Anticancer mechanism of compound 22 by examining protein expression changes in HepG2 cells using quantitative proteomics. Our findings indicated that 22 induced G1/S phase cell cycle arrest and, In a dose-dependent manner, inhibited CDK4 and CyclinD1 expression while upregulating P21. Moreover, 22 promoted the accumulation of autophagosomes and the proteins LC3 and PINK1, enhancing Autophagy and Mitophagy in HepG2 cells. Collectively, compound 22 might serve as a novel Autophagy agonist with Anticancer properties.

Keywords

20-Deoxyingenol derivatives; Cytotoxicity; Regularity of esterified substitution assignment.

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