Design, synthesis and mechanistic study of new dual targeting HDAC/tubulin inhibitors

Future Med Chem. 2024 Apr;16(7):601-622. doi: 10.4155/fmc-2023-0336. Epub 2024 Mar 4.

Abstract

Aim: The purpose of this work is to create and synthesize a new class of chemicals: 3-cyano-2-substituted pyridine compounds with expected multitarget inhibition of histone deacetylase (HDAC) and tubulin. Materials & methods: The target compounds (3a-c, 4a-c and 5a-c) were synthesized utilizing 6-(4-methoxyphenyl)-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-cyanopyridine, with various linkers and zinc-binding groups (ZBGs). Results: Most of the tested compounds showed promising growth inhibition, and hydroxamic acid-containing hybrids possessed higher HDAC inhibition than other ZBGs. Compound 4b possessed the highest potency; however, it showed the most tubulin polymerization inhibition. Docking studies displayed good binding into HDAC1 and six pockets and tubulin polymerization protein. Conclusion: Compound 4b could be considered a good antitumor candidate to go further into in vivo and clinical studies.

Keywords: HDAC; capping; cyanopyridine; docking; multitargeting; tubulin.

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Cell Line, Tumor
  • Cell Proliferation
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase Inhibitors* / chemistry
  • Histone Deacetylases / metabolism
  • Structure-Activity Relationship
  • Tubulin / metabolism
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology

Substances

  • Histone Deacetylase Inhibitors
  • Tubulin
  • Tubulin Modulators
  • Antineoplastic Agents
  • Histone Deacetylases