4.7 Article

Effective enmein-type mimics of clinical candidate HAO472: Design, synthesis and biological evaluation

期刊

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 171, 期 -, 页码 169-179

出版社

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.03.046

关键词

Amino acid ester; Enmein-type diterpenoid; Antiproliferative activity; Selectivity; Apoptosis

资金

  1. National Natural Science Foundation of China [21772124, 21502121]
  2. General Scientific Research Projects of Department of Education in Liaoning Province [2017LQN05]
  3. Natural Science Foundation of Liaoning Province [20170540858]
  4. Career Development Support Plan for Young and Middle-aged Teachers in Shenyang Pharmaceutical University
  5. Key Laboratory of Quality Control of TCM of Liaoning Province [17-137-1-00]

向作者/读者索取更多资源

A series of enmein-type diterpenoid amino acid ester derivatives (14-22) were designed and synthesized according to L-alanine-(14-oridonin) ester trifluoroacetate (clinical candidate HAO472). Their antiproliferative activities were tested against SGC-7901, Bel-7402, HL-60, PC-3, A549 and K562 cancer cell lines and L-02 normal liver cells. The results showed that compound 19 possessed the most potent cytotoxicity with IC50 s at sub-micromolar level against human hepatoma Bel-7402 and chronic myelogenous leukemia K562 cells and more potent than L-alanine-(14-oridonin) ester (23). More importantly, 19 displayed 70-fold less cytotoxicity than parent 3 (IC50 = 25.47 mu M) against L-02 cells, which exhibited certain selectivity. Further mechanism study in Bel-7402 cells revealed that 19 could induce apoptosis, G(1) phase cell cycle arrest and mitochondria[ dysfunction. Western blot results of caspase-3, Bax and cytochrome c upregulation and pro-caspase-3, Bcl-2 and Bcl-xL downregulation confirmed the intrinsic pathways. Overall, these data collectively demonstrated the high efficiency and selectivity of 19, c-phenylalanine-enmein-type diterpenoid ester, which inspires further and effective application as a potential antitumor candidate. (C) 2019 Elsevier Masson SAS. All rights reserved.

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