Journal
BIOORGANIC CHEMISTRY
Volume 115, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2021.105220
Keywords
Tubulin; Restriction configuration; Pyrazolo[1, 5-a]pyrimidine; Colchicine-binding site
Funding
- National Natural Science Foundation of China [81673293]
- China Postdoctoral Science Foundation [2018M641715]
- Liaoning Revitalization Talents Program [XLYC1802072, XLYC2007073]
- Natural Science Foundation of Liaoning [2020-MS-190]
- Shenyang Science & Technology Bureau Item [20-205-4-026]
- Shenyang Science and Technology Innovation Talents Program [RC200441]
- Plan for Development of Young Scholars of Shenyang pharmaceutical university [ZQN2018002]
- Program for Innovative Research Team of the Ministry of Education
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The newly designed compound 6d showed significant antiproliferative activity against MCF-7 cancer cells, inhibiting cancer cell growth and migration through multiple pathways.
Two series of 2,7-diaryl-pyrazolo[1,5-a]pyrimidines as tubulin polymerization inhibitors were designed to restrict bioactive configuration of (E,Z)-vinylogous CA-4. All of the target compounds were synthesized and then evaluated for their in vitro antiproliferative activities against three cancer cell lines (MCF-7, SGC-7901 and A549). Among them, 6d exhibited the most potent antiproliferative activity against the MCF-7 with IC50 value of 0.047 mu M. Moreover, 6d significantly inhibited tubulin polymerization, disrupted microtubule networks, arrested cell cycle at G2/M phase, induced apoptosis and hindered cancer cell migration. Colchicine competition assay and molecular docking studies suggested that 6d could interact with tubulin by binding to the colchicine site.
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