2. Academic Validation
  3. Design, synthesis, and structure-activity relationship study of novel plinabulin derivatives as anti-tumor agents based on the co-crystal structure

Design, synthesis, and structure-activity relationship study of novel plinabulin derivatives as anti-tumor agents based on the co-crystal structure

  • Mol Divers. 2024 Apr 23. doi: 10.1007/s11030-024-10835-7.
Shixiao Wang # 1 2,  Changjiang Zhong # 1,  Feifei Li 2,  Zhongpeng Ding 3 4,  Yu Tang 5 6,  Wenbao Li 7
Affiliations

Affiliations

  • 1 School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • 2 Shenzhen Huahong Marine Biomedical Co., Ltd., Shenzhen, 518002, China.
  • 3 Shenzhen Huahong Marine Biomedical Co., Ltd., Shenzhen, 518002, China. dingzhongpeng@lyu.edu.cn.
  • 4 Medical College, Linyi University, Shuangling Road, Linyi, 276000, China. dingzhongpeng@lyu.edu.cn.
  • 5 School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China. tangyu@ouc.edu.cn.
  • 6 Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China. tangyu@ouc.edu.cn.
  • 7 Shenzhen Huahong Marine Biomedical Co., Ltd., Shenzhen, 518002, China. liwenbao@chinamarine.com.
  • # Contributed equally.
PMID: 38652366 DOI: 10.1007/s11030-024-10835-7
Abstract

Plinabulin, a 2, 5-diketopiperazine-type tubulin inhibitor derived from Marine natural products, is currently undergoing Phase III clinical trials for the treatment of non-small cell lung Cancer (NSCLC) and chemotherapy-induced neutropenia (CIN). To obtain novel 2, 5-diketopiperazine derivatives with higher biological activity, we designed and synthesized two series of 37 plinabulin derivatives at the C-ring, based on the co-crystal structure of compound 1 and tubulin. Their structures were characterized using NMR and HRMS. All compounds were screened in vitro using the lung Cancer cell line NCI-H460 using the MTT method, and the compounds with better activity were further screened in BxPC-3 and HT-29 cells. The compounds 16c (IC50 = 2.0, NCI-H460; IC50 = 1.2 nM, BxPC-3; IC50 = 1.97 nM, HT-29) and 26r (IC50 = 0.96, NCI-H460; IC50 = 0.66 nM, BxPC-3; IC50 = 0.61 nM, HT-29) had the best activity. The cytotoxic activity of compound 26r against various tumor cell lines occurred at less than 1 nM.

Keywords

Anticancer; Co-crystal structure; Plinabulin derivatives; SAR study.

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