Synthesis, Biological Evaluation, and Molecular Docking of Arylpyridines as Antiproliferative Agent Targeting Tubulin
- ACS Med Chem Lett. 2020 Jul 15;11(8):1611-1619. doi: 10.1021/acsmedchemlett.0c00278.
- 1. Innovation Program of Drug Research on Neurological and Metabolic Diseases, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
- 2. Key Laboratory of Mental Health of the Ministry Education, Southern Medical University, Guangzhou 510515, China.
- 3. Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Mimicking different pharmacophoric units into one scaffold is a promising structural modification tool to design new drugs with enhanced biological properties. To continue our research on the tubulin inhibitors, the synthesis and biological evaluation of arylpyridine derivatives (9-29) are described herein. Among these compounds, 6-arylpyridines (13-23) bearing benzo[d]imidazole side chains at the 2-position of pyridine ring displayed selective antiproliferative activities against HT-29 cells. More interestingly, 2-trimethoxyphenylpyridines 25, 27, and 29 bearing benzo[d]imidazole and benzo[d]oxazole side chains displayed more broad-spectrum antitumor activities against all tested Cancer cell lines. 29 bearing a 6-methoxybenzo[d]oxazole group exhibited comparable activities against A549 and U251 cells to combretastatin A-4 (CA-4) and lower cytotoxicities than CA-4 and 5-Fu. Further investigations revealed 29 displays strong tubulin polymerization inhibitory activity (IC50 = 2.1 μM) and effectively binds at the colchicine binding site and arrests the cell cycle of A549 in the G2/M phase by disrupting the microtubules network.