Structure-Activity Relationship Study of Novel 6-Aryl-2-benzoyl-pyridines as Tubulin Polymerization Inhibitors with Potent Antiproliferative Properties.

Abstract

We recently reported the crystal structure of tubulin in complex with a colchicine binding site inhibitor (CBSI), ABI-231, having 2-aryl-4-benzoyl-imidazole (ABI). Based on this and additional crystal structures, here we report the structure-activity relationship study of a novel series of pyridine analogues of ABI-231, with compound 4v being the most potent one (average IC50 ∼ 1.8 nM) against a panel of cancer cell lines. We determined the crystal structures of another potent CBSI ABI-274 and 4v in complex with tubulin and confirmed their direct binding at the colchicine site. 4v inhibited tubulin polymerization, strongly suppressed A375 melanoma tumor growth, induced tumor necrosis, disrupted tumor angiogenesis, and led to tumor cell apoptosis in vivo. Collectively, these studies suggest that 4v represents a promising new generation of tubulin inhibitors.

• Authors: Hao Chen, Shanshan Deng, Yuxi Wang, Najah Albadari, Gyanendra Kumar, Dejian Ma, Weimin Li, Stephen W White, Duane D Miller, Wei Li
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 2 Pg. 827-846 (01 23 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 31860298 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Pyridines
• Tubulin Modulators
• Colchicine

Topics

• Angiogenesis Inhibitors (chemical synthesis, pharmacology)
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colchicine (chemistry)
• Crystallography, X-Ray
• Drug Resistance, Neoplasm (drug effects)
• Drug Screening Assays, Antitumor
• Female
• Humans
• Models, Molecular
• Pyridines (chemical synthesis, pharmacology)
• Structure-Activity Relationship
• Tubulin Modulators (chemical synthesis, pharmacology)