Discovery of 4-amino-2-(thio)phenol derivatives as novel protein kinase and angiogenesis inhibitors for the treatment of cancer: Synthesis and biological evaluation. Part II

• A series of 4-amino-2-(thio)phenol derivatives were synthesized.
• The compounds were evaluated as inhibitors of protein kinase and angiogenesis.
• Some of them exhibited remarkably in vitro protein kinase inhibition.
• Anti-angiogenic activity of 5i was similar to clinically used drug pazopanib.

A novel series of 4-amino-2-(thio)phenol derivatives were well synthesized. The preliminary biological test revealed that several compounds displayed high specific protein kinase and angiogenesis inhibitory activities compared with previous work mainly because of the substitution of sulfonamide structure for amide fragment. Among which, compound 5i was identified to inhibit protein kinase B/AKT (IC50 = 1.26 μM) and ABL tyrosine kinase (IC50 = 1.50 μM) effectively. Meanwhile, compound 5i demonstrated competitive in vitro antiangiogenic activities to Pazopanib in both human umbilical vein endothelial cell (HUVEC) tube formation assay and the rat thoracic aorta rings test.

Key compound 5i and its calculated binding mode in the ATP-binding pocket of AKT kinase.Figure optionsDownload as PowerPoint slide