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Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure.

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资源类型：
Pubmed体系：
作者：
Zhongpeng Ding[a] ; Mingxu Ma[a] ; Changjiang Zhong[a] ; Shixiao Wang[c] ; Zhangyu Fu[a] ; Yingwei Hou[a,c] ; Yuqian Liu[a] ; Lili Zhong[a] ; Yanyan Chu[c] ; Feng Li[a,c] ; Cai Song[d] ; Yuxi Wang[e] ; Jinliang Yang[e] ; Wenbao Li[a,b,c,*1] ;
机构： [a]School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China [b]Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China [c]Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China [d]Shenzhen Institute, Guangdong Ocean University, Shenzhen 518116, China [e]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy and Cancer, Chengdu 610041, China
出处：
DOI： 10.1016/j.bmc.2019.115186
ISSN：

关键词： Plinabulin Phenoxy-diketopiperazine-type derivative Co-crystal structure SAR study Molecular docking

摘要：
The co-crystal structure of Compound 6b with tubulin was prepared and solved for indicating the binding mode and for further optimization. Based on the co-crystal structures of tubulin with plinabulin and Compound 6b, a total of 27 novel A/B/C-rings plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human lung cancer NCI-H460 cell line. The optimum phenoxy-diketopiperazine-type Compound 6o exhibited high potent cytotoxicity (IC50 = 4.0 nM) through SAR study of three series of derivatives, which was more potent than plinabulin (IC50 = 26.2 nM) and similar to Compound 6b (IC50 = 3.8 nM) against human lung cancer NCI-H460 cell line. Subsequently, the Compound 6o was evaluated against other four human cancer cell lines. Both tubulin polymerization assay and immunofluorescence assay showed that Compound 6o could inhibit microtubule polymerization efficiently. Furthermore, theoretical calculation of the physical properties and molecular docking were elucidated for these plinabulin derivatives. The binding mode of Compound 6o was similar to Compound 6b based on the result of molecular docking. The theoretical calculated LogPo/w and PCaco of Compound 6o were better than Compound 6b, which could enhance its cytostatic activity. Therefore, Compound 6o might be developed as a novel potent anti-microtubule agent. Copyright © 2019. Published by Elsevier Ltd.

基金：
This work was supported by “Zhufeng Scholar Program” of Ocean University of China (841412016), and Aoshan Talents Cultivation Program of Qingdao National Laboratory for Marine Science and Technology (No. 2017ASTCP-OS08) to Dr. Wenbao Li.
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2020]版：
大类 | 3 区 医学
小类 | 2 区 有机化学 3 区 生化与分子生物学 3 区 药物化学
最新[2023]版：
大类 | 3 区 医学
小类 | 2 区 有机化学 3 区 生化与分子生物学 3 区 药物化学
第一作者：
第一作者机构： [a]School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
共同第一作者：
通讯作者：
通讯机构： [a]School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China [b]Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China [c]Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China [*1]School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China
推荐引用方式(GB/T 7714)：
Zhongpeng Ding,Mingxu Ma,Changjiang Zhong,et al.Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure.[J].Bioorganic & medicinal chemistry.2020,28(1):115186.doi:10.1016/j.bmc.2019.115186.
APA：
Zhongpeng Ding,Mingxu Ma,Changjiang Zhong,Shixiao Wang,Zhangyu Fu...&Wenbao Li.(2020).Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure..Bioorganic & medicinal chemistry,28,(1)
MLA：
Zhongpeng Ding,et al."Development of novel phenoxy-diketopiperazine-type plinabulin derivatives as potent antimicrotubule agents based on the co-crystal structure.".Bioorganic & medicinal chemistry 28..1(2020):115186

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