Discovery of novel 2-aryl-3-sulfonamido-pyridines (HoAns) as microtubule polymerization inhibitors with potent antitumor activities
| Autor: | Xiao Liang, Shilong Ying, Hongchuan Jin, Xinyang Hu, Heping Zhu, Quan He, Ping Song, Bingluo Zhou, Keqiang Shi, Yuanjiang Pan, Mingteng Xiong |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Vinca
Pyridines Antineoplastic Agents 01 natural sciences Microtubules Microtubule polymerization 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship Microtubule Drug Discovery medicine Colchicine Humans Mitosis 030304 developmental biology Pharmacology 0303 health sciences biology Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Cancer General Medicine biology.organism_classification medicine.disease 0104 chemical sciences Tubulin Apoptosis Drug Design biology.protein Cancer research |
| Zdroj: | European journal of medicinal chemistry. 211 |
| ISSN: | 1768-3254 |
| Popis: | Microtubules play a vital role in cell mitosis. Drugs targeting taxol or vinca binding site of tubulin have been proved an effective way to against cancer. However, drug resistance and cancer recurrence are inevitable, there is an urgent need to search for new microtubule-targeting agents (MTAs). In our study, a series of novel 2-aryl-3-sulfonamido-pyridines (HoAns) had been designed, synthesized, and evaluated for their antiproliferative activities in vitro and in vivo. Among them, compound HoAn32 exhibited the most potent activity with IC50 values ranging from 0.170 to 1.193 μM in a panel of cancer cell lines. Mechanism studies indicated that compound HoAn32 bound to the colchicine site of β-tubulin, resulting in colony formation inhibition, G2/M phase cell cycle arrest, cell apoptosis as well as increased the generation of ROS in both RKO and SW620 cells. In addition, compound HoAn32 showed potent anti-vascular activity in vitro. Furthermore, compound HoAn32 also exhibited outstanding antitumor activity in SW620 xenograft tumor models without observable toxic effects, which was more potent than that of ABT-751. In conclusion, our findings suggest that compound HoAn32 may be a promising microtubule destabilizing agent and deserves for further development in cancer therapy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect