2. Academic Validation
  3. Design, synthesis and anti-tumor evaluation of plinabulin derivatives as potential agents targeting β-tubulin

Design, synthesis and anti-tumor evaluation of plinabulin derivatives as potential agents targeting β-tubulin

  • Bioorg Med Chem Lett. 2023 Jul 15:91:129370. doi: 10.1016/j.bmcl.2023.129370.
Shiyuan Fang 1,  Shijie Bi 1,  Yannan Li 1,  Shuai Tian 2,  Huixin Xu 1,  Lei Fu 1,  Shixiao Wang 1,  Yu Tang 3,  Peiju Qiu 4
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Yushan Road, Qingdao 266003, China.
  • 2 Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China.
  • 3 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Yushan Road, Qingdao 266003, China; Laboratory for Marine Drugs and Bioproducts Qingdao National Laboratory for Marine Science and Technology Qingdao 266237, China. Electronic address: tangyu@ouc.edu.cn.
  • 4 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Yushan Road, Qingdao 266003, China; Center for Innovation Marine Drug Screening &Evaluation, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China.
PMID: 37301522 DOI: 10.1016/j.bmcl.2023.129370
Abstract

Plinabulin is a promising microtubule destabilizing agent in phase 3 clinical stage for treating non-small cell lung Cancer. However, the high toxicity and the poor water solubility of plinabulin limited its use and more plinabulin derivatives need to be explored. Here, two series of 29 plinabulin derivatives were designed, synthesized and evaluated for their anti-tumor effect against three types of Cancer cell lines. Most of derivatives exerted obvious inhibition to the proliferation of the cell lines tested. Among them, compound 11c exerted stronger efficiency than plinabulin, and the reason might be the additional hydrogen bond between the nitrogen atom of the indole ring in compound 11c and Gln134 of β-tubulin. Immunofluorescence assay showed that compound 11c at 10 nM significantly disrupted tubulin structure. Compound 11c also significantly induced G2/M cell cycle arrest and Apoptosis in dose dependent manner. These results suggest that compound 11c might be a potential candidate for Cancer treatment as antimicrotubule agent.

Keywords

Antitumor; Apoptosis; Cell cycle; Plinabulin derivatives; β-Tubulin.

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