Design, synthesis, and antitumor evaluation of quinazoline-4-tetrahydroquinoline chemotypes as novel tubulin polymerization inhibitors targeting the colchicine site

Eur J Med Chem. 2025 Feb 5:283:117139. doi: 10.1016/j.ejmech.2024.117139. Epub 2024 Dec 6.

Abstract

We designed, synthesized, and evaluated the antitumor activity of a series of novel quinazoline-4-(6-methoxytetrahydroquinoline) analogues. Among the tested compounds, 4a4 exhibited the most potent antiproliferative activities across four human cancer cell lines with half-maximal inhibitory concentration (IC50) values ranging from 0.4 to 2.7 nM, more potent than the lead compound. The 2.71 Å resolution co-crystal structure of 4a4 with tubulin (PDB code: 8YER) confirmed its critical binding at the colchicine site. Moreover, 4a4 inhibited the polymerization of tubulin, colony formation, and tumor cell migration, while inducing G2/M phase arrest and apoptosis. In vivo, 4a4 significantly delayed primary tumor growth in the SKOV3 xenograft model without obvious side effect. Our research enhances the structure-activity relationships (SARs) understanding of the quinazoline-4-tetrahydroquinoline scaffold and provides new insights for potential structural optimization and the development of novel colchicine binding site inhibitors (CBSIs).

Keywords: Antitumor; Co-crystal structure; Colchicine binding site inhibitors (CBSIs); Quinazoline-4-tetrahydroquinoline; Structure-activity relationship (SAR); Tubulin.

MeSH terms

  • Animals
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Apoptosis / drug effects
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation* / drug effects
  • Colchicine* / chemistry
  • Colchicine* / metabolism
  • Colchicine* / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor*
  • Female
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Polymerization / drug effects
  • Quinazolines* / chemical synthesis
  • Quinazolines* / chemistry
  • Quinazolines* / pharmacology
  • Quinolines* / chemical synthesis
  • Quinolines* / chemistry
  • Quinolines* / pharmacology
  • Structure-Activity Relationship
  • Tubulin Modulators* / chemical synthesis
  • Tubulin Modulators* / chemistry
  • Tubulin Modulators* / pharmacology
  • Tubulin* / metabolism

Substances

  • Antineoplastic Agents
  • Tubulin Modulators
  • Quinolines
  • Colchicine
  • Quinazolines
  • Tubulin