The inhibition profiles of 4'-acylpyrrole-5-fluoroindolin-2-ones with a C-3' side chain for VEGFR2, PDGFR-β, and FGFR-1 protein kinases

In this study, we reported the inhibition profiles of 4 '-acylpyrrole-5-fluoroindolin-2-one 3 with a C-3 ' side chain for VEGFR2, PDGFR-beta, and FGFR-1 protein kinases. The pyrrole-fused cyclohexanone moiety provided 3 with the best potency to inhibit the three kinases, and the C-3 ' side chains contributed to the different inhibition profiles of 3. Compound 3b with a C-3 ' 2-carboxylethyl side chain showed good potency for the three kinase (IC50: 25-260 nM), and compound 3g with a N,N-dialkyl-2-carbamoylethyl side chain was more active for VEGFR2 (IC50: 59 nM) and PDGFR-beta (IC50: 16 nM) than FGFR-1 (IC50: 1.7 mu M). The C-3 ' 3-(dialkylamino)propyl side chain accomplished 3h-j as selective PDGFR-beta inhibitors (IC50: 7.8-13 nM). Compound 3b was further investigated and found potent to inhibit VEGF- and FGF-dependent cell proliferation with moderate in vivo anticancer activity. Results from docking simulations revealed that the interactions of 3b with VEGFR2 and FGFR-1 which could account for the different inhibition profiles of 3.