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

Eur J Med Chem. 2019 Jun 1:171:169-179. doi: 10.1016/j.ejmech.2019.03.046.

Xu Hu ¹, Ziyi Bai ², Jian Qiao ², Haonan Li ¹, Shengtao Xu ³, Xianhua Wang ⁴, Yongnan Xu ⁵, Jinyi Xu ³, Huiming Hua ⁶, Dahong Li ⁷

Affiliations

1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China.
2 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China.
3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
4 School of Public Health, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, PR China.
5 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China; School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China. Electronic address: ynanxu@hotmail.com.
6 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China. Electronic address: huimhua@163.com.
7 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, PR China. Electronic address: lidahong0203@163.com.

PMID: 30921757 DOI: 10.1016/j.ejmech.2019.03.046

Abstract

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.

Keywords

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

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