2. Academic Validation
  3. Discovery of 6-aryl-2-(3,4,5-trimethoxyphenyl)thiazole[3,2-b][1,2,4]triazoles as potent tubulin polymerization inhibitors

Discovery of 6-aryl-2-(3,4,5-trimethoxyphenyl)thiazole[3,2-b][1,2,4]triazoles as potent tubulin polymerization inhibitors

  • Eur J Med Chem. 2023 Aug 5:256:115402. doi: 10.1016/j.ejmech.2023.115402.
Na Li 1,  Qi Guan 1,  Yilang Hong 1,  Bowen Zhang 1,  Mi Li 1,  Xuewen Li 2,  Bo Li 3,  Lan Wu 4,  Weige Zhang 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
  • 2 School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Street, Heping District, Shenyang, 110002, China.
  • 3 School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, 117 Nanjing North Street, Heping District, Shenyang, 110002, China. Electronic address: [email protected].
  • 4 Department of Geratology, The First Affiliated Hospital, Chinese Medical University, Shenyang, 110001, China. Electronic address: [email protected].
  • 5 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: [email protected].
PMID: 37182330 DOI: 10.1016/j.ejmech.2023.115402
Abstract

Tubulin/colchicine-binding site inhibitors (CBSIs) co-crystal structures play an important role in the exploration of novel small molecules for oncotherapy. Based on the analysis of the binding models of tubulin and reported CBSIs, a series of 6-aryl-2-(3,4,5-trimethoxyphenyl)thiazole[3,2-b][1,2,4]triazoles were designed as potential tubulin polymerization inhibitors by binding to distinct colchicine domain of tubulin. Among the compounds synthesized, 7w not only shown noteworthy potency against SGC-7901 Cancer cell line (IC50 = 0.21 μM) but also exhibited lower cytotoxicity than colchicine in normal cell line (HUVEC). The mechanism studies elucidated that 7w could cause the Apoptosis of Cancer cells by inhibiting tubulin polymerization to trigger G2/M arrest. In 4T1-xenograft mice model, 7w significantly inhibited tumor growth without losing weight, demonstrating a promising potential for further development with a unique binding mode at the colchicine-binding site.

Keywords

Antiproliferative activity; Colchicine-binding site inhibitor; Molecular modeling; Thiazole[3,2-b][1,2,4]triazole.

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