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

• Published in: European journal of medicinal chemistry 2019-06, Vol.171, p.169-179
• Main Authors: Hu, Xu, Bai, Ziyi, Qiao, Jian, Li, Haonan, Xu, Shengtao, Wang, Xianhua, Xu, Yongnan, Xu, Jinyi, Hua, Huiming, Li, Dahong
• Format: Article
• Language: English
• Subjects: Amino acid ester; Antiproliferative activity; Apoptosis; Enmein-type diterpenoid; Selectivity
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.03.046

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 μM) against L-02 cells, which exhibited certain selectivity. Further mechanism study in Bel-7402 cells revealed that 19 could induce apoptosis, G1 phase cell cycle arrest and mitochondrial 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, l-phenylalanine-enmein-type diterpenoid ester, which inspires further and effective application as a potential antitumor candidate. [Display omitted] •Enmein-type diterpenoid amino acid ester derivatives were synthesized.•All target derivatives showed antiproliferative activities to some extent.•19 showed potent activities and good selectivity between normal and tumor cells.•19 could induce apoptosis and arrest cell cycle at G1 phase in Bel-7402 cells.•19 induced Bel-7402 cells apoptosis via the mitochondria-related pathway.