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.
Hao Chen  1 ,  Shanshan Deng  1 ,  Najah Albadari  1 ,  Mi-Kyung Yun  2 ,  Sicheng Zhang  1 ,  Yong Li  3 ,  Dejian Ma  1 ,  Deanna N Parke  4 ,  Lei Yang  3 ,  Tiffany N Seagroves  4 ,  Stephen W White  2 ,  Duane D Miller  1 ,  Wei Li  1
Affiliations
  • 1. Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 2. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 3. Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.
  • 4. Department of Pathology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
PMID: 34378386 DOI: 10.1021/acs.jmedchem.1c00715
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.