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Design, Synthesis, and Biological Evaluation of Stable Colchicine-Binding Site Tubulin Inhibitors 6-Aryl-2-benzoyl-pyridines as Potential Anticancer Agents
- Source :
- J Med Chem
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 2021.
-
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.
- Subjects :
- Male
Pyridines
Antineoplastic Agents
Mice, SCID
Article
Structure-Activity Relationship
chemistry.chemical_compound
Drug Stability
Mice, Inbred NOD
Tubulin
In vivo
Cell Line, Tumor
Neoplasms
Drug Discovery
Animals
Humans
Neoplasm Metastasis
Mode of action
Cell Proliferation
Binding Sites
Molecular Structure
biology
Aryl
Xenograft Model Antitumor Assays
Tubulin Modulators
In vitro
G2 Phase Cell Cycle Checkpoints
Multiple drug resistance
chemistry
Biochemistry
Drug Design
Microsomes, Liver
biology.protein
Microsome
Molecular Medicine
Female
Drug Screening Assays, Antitumor
Lead compound
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 64
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....3d4f84c1e5a7e0705da120cf921aefa4