Discovery of highly potent tubulin polymerization inhibitors: Design, synthesis, and structure-activity relationships of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidines
| Autor: | Lin Chen, Xian-Sen Huo, Fang Yang, Xie-Er Jian, Jie Ou-Yang, Dong-Xin Lv, Jin-Jun Rao, Pei-Liang Zhao, You Wenwei |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Pyrimidine
Poly ADP ribose polymerase Antineoplastic Agents Apoptosis 01 natural sciences Cell Line Polymerization HeLa Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Tubulin Drug Discovery Humans Cyclin B1 Cell Proliferation 030304 developmental biology Pharmacology 0303 health sciences Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Organic Chemistry General Medicine biology.organism_classification Embryonic stem cell Tubulin Modulators 0104 chemical sciences Molecular Docking Simulation Pyrimidines chemistry Biochemistry Cancer cell Drug Screening Assays Antitumor Selectivity |
| Zdroj: | European Journal of Medicinal Chemistry. 220:113449 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2021.113449 |
| Popis: | By removing 5-methyl and 6-acetyl groups in our previously reported compound 3, we designed a series of novel 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine derivatives as potential tubulin polymerization inhibitors. Among them, compound 5e displayed low nanomolar antiproliferative efficacy on HeLa cells which was 166-fold higher than the lead analogue 3. Interestingly, 5e displayed significant selectivity in inhibiting cancer cells over HEK-293 (normal human embryonic kidney cells). In addition, 5e dose-dependently arrested HeLa in G2/M phase through the alterations of the expression levels of p-cdc2 and cyclin B1, and caused HeLa cells apoptosis by regulation of expressions of cleaved PARP. Further evidence demonstrated that 5e effectively inhibited tubulin polymerization and was 3-fold more powerful than positive control CA-4. Moreover, molecular docking analysis indicated that 5e overlapped well with CA-4 in the colchicine-binding site. These studies demonstrated that 2,7-diaryl-[1,2,4]triazolo[1,5-a]pyrimidine skeleton might be used as the leading unit to develop novel tubulin polymerization inhibitors as potential anticancer agents. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect