2. Academic Validation
  3. Design, synthesis and biological evaluation of anti-pancreatic cancer activity of plinabulin derivatives based on the co-crystal structure

Design, synthesis and biological evaluation of anti-pancreatic cancer activity of plinabulin derivatives based on the co-crystal structure

  • Bioorg Med Chem. 2018 May 1;26(8):2061-2072. doi: 10.1016/j.bmc.2018.03.005.
Zhangyu Fu 1,  Yingwei Hou 2,  Cunpeng Ji 3,  Mingxu Ma 1,  Zhenhua Tian 1,  Mengyan Deng 1,  Lili Zhong 1,  Yanyan Chu 2,  Wenbao Li 4
Affiliations

Affiliations

  • 1 School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
  • 2 School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China.
  • 3 Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China.
  • 4 School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China; Innovation Center for Marine Drug Screening and Evaluation, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266071, China; Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China. Electronic address: wbli92128@ouc.edu.cn.
PMID: 29571653 DOI: 10.1016/j.bmc.2018.03.005
Abstract

Based on the co-crystal structures of tubulin with plinabulin and Compound 1 (a derivative of plinabulin), a total of 18 novel plinabulin derivatives were designed and synthesized. Their biological activities were evaluated against human pancreatic Cancer BxPC-3 cell lines. Two novel Compounds 13d and 13e exhibited potent activities with IC50 at 1.56 and 1.72 nM, respectively. The tubulin polymerization assay indicated that these derivatives could inhibit microtubule polymerization. Furthermore, the interaction between tubulin and these compounds were elucidated by molecular docking. The binding modes of Compounds 13d and 13e were similar to the co-crystal structure of Compound 1. H-π interaction was observed between the aromatic hydrogen of thiophene moiety with Phe20, which could enhance their binding affinities.

Keywords

Co-crystal structure; Pancreatic cancer; Plinabulin derivatives; Tubulin.

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