Design, Synthesis, and Biological Evaluation of Stable Colchicine-Binding Site Tubulin Inhibitors 6-Aryl-2-benzoyl-pyridines as Potential Anticancer Agents

J Med Chem. 2021 Aug 26;64(16):12049-12074. doi: 10.1021/acs.jmedchem.1c00715. Epub 2021 Aug 11.

Abstract

We previously reported a potent tubulin inhibitor CH-2-77. In this study, we optimized the structure of CH-2-77 by blocking metabolically labile sites and synthesized a series of CH-2-77 analogues. Two compounds, 40a and 60c, preserved the potency while improving the metabolic stability over CH-2-77 by 3- to 4-fold (46.8 and 29.4 vs 10.8 min in human microsomes). We determined the high-resolution X-ray crystal structures of 40a (resolution 2.3 Å) and 60c (resolution 2.6 Å) in complex with tubulin and confirmed their direct binding at the colchicine-binding site. In vitro, 60c maintained its mode of action by inhibiting tubulin polymerization and was effective against P-glycoprotein-mediated multiple drug resistance and taxol resistance. In vivo, 60c exhibited a strong inhibitory effect on tumor growth and metastasis in a taxol-resistant A375/TxR xenograft model without obvious toxicity. Collectively, this work showed that 60c is a promising lead compound for further development as a potential anticancer agent.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / therapeutic use*
  • Binding Sites
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Drug Stability
  • Female
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Neoplasm Metastasis / prevention & control
  • Neoplasms / drug therapy*
  • Pyridines / chemical synthesis
  • Pyridines / metabolism
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use*
  • Structure-Activity Relationship
  • Tubulin / chemistry
  • Tubulin / metabolism*
  • Tubulin Modulators / chemical synthesis
  • Tubulin Modulators / metabolism
  • Tubulin Modulators / pharmacokinetics
  • Tubulin Modulators / therapeutic use*
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Pyridines
  • Tubulin
  • Tubulin Modulators