Structure-activity relationships of natural quinone vegfrecine analogs with potent activity against VEGFR-1 and -2 tyrosine kinases.

Abstract

A series of analogs of vegfrecine, a natural quinone vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, was synthesized via oxidative amination of 2,5-dihydroxybenzamide with functionalized arylamine followed by ammonolysis and substitution of the quinone ring. The inhibitory activities of the analogs against the VEGFR-1 and -2 tyrosine kinases were assayed in vitro with the aim to identify a compound suitable to treat cancer and inflammatory diseases. Alterations of the functionality of the phenyl group, substitution of the quinone ring, and oxidative cyclization of the 1-carboxamide-2-aminoquinone moiety to form an isoxazole quinone ring were examined. Introduction of halo- and alkyl-substituents at the 5'-position of the phenyl ring resulted in potent inhibition of the VEGFR-1 and -2 tyrosine kinases. In particular, structural modification at C-5' on the phenyl ring was shown to significantly affect the selectivity of the inhibition between the VEGFR-1 and -2 tyrosine kinases. Compound 8, 5'-methyl-vegfrecine, showed superior selectivity toward the VEGFR-2 tyrosine kinase over the VEGFR-1 tyrosine kinase.

• Authors: Hayamitsu Adachi, Chisato Nosaka, Sonoko Atsumi, Koichi Nakae, Yoji Umezawa, Ryuichi Sawa, Yumiko Kubota, Chie Nakane, Masabumi Shibuya, Yoshio Nishimura
• Journal: The Journal of antibiotics (J Antibiot (Tokyo)) Vol. 74 Issue 10 Pg. 734-742 (10 2021) ISSN: 1881-1469 [Electronic] England
• PMID: 34282315 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to the Japan Antibiotics Research Association.

Chemical References

• Antineoplastic Agents
• Benzoquinones
• vegfrecine
• Vascular Endothelial Growth Factor Receptor-1
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzoquinones (chemistry, pharmacology)
• Cell Survival (drug effects)
• Drug Discovery
• Mice
• Molecular Docking Simulation
• Molecular Structure
• NIH 3T3 Cells
• Structure-Activity Relationship
• Vascular Endothelial Growth Factor Receptor-1 (antagonists & inhibitors)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)