Design, synthesis and biological evaluation of O-linked indoles as VEGFR-2 kinase inhibitors (I)

Inhibition of VEGFR-2 signaling pathway has already become one of the most promising approaches for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of a series of O-linked indoles as potent inhibitors of VEGFR-2. Among these compounds, 18 showed significant anti-angiogenesis activities via VEGFR-2 in enzymatic proliferation assays, with IC50 value of 3.8 nmol/L. Kinase selectivity profiling revealed that 18 was a multitargeted inhibitor, and it also exhibited good potency against VEGFR-1, PDGFR-α and β.

Graphical abstractIn an effort to discover potent VEGFR-2 inhibitors, a series of 2,4 or 4,6-disubstituted O-linked indoles derivatives were designed and synthesized. The structural activity relationships led to identification of a potential VEGFR-2 inhibitor compound 18.Figure optionsDownload full-size imageDownload as PowerPoint slide