Structural optimization and evaluation of novel 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole derivatives as potential VEGFR-2/PDGFRβ inhibitors.

BACKGROUND: Tumor angiogenesis, essential for tumor growth and metastasis, is tightly regulated by VEGF/VEGFR and PDGF/PDGFR pathways, and therefore blocking those pathways is a promising therapeutic target. Compared to sunitinib, the C(5)-Br derivative of 2-pyrrolidone-fused (2-oxoindolin-3-ylidene)methylpyrrole has significantly greater in vitro activities against VEGFR-2, PDGFRβ, and tube formation. RESULTS AND DISCUSSION: The objective of this study was to perform further structural optimization, which revealed certain new products with even more potent anti-tumor activities, both cellularly and enzymatically. Of these, 15 revealed ten- and eightfold stronger potencies against VEGFR-2 and PDGFRβ than sunitinib, respectively, and showed selectivity against HCT116 with a favorable selective index (SI > 4.27). The molecular docking results displayed that the ligand-protein binding affinity to VEGFR-2 could be enhanced by introducing a hydrogen-bond-donating (HBD) substituent at C(5) of (2-oxoindolin-3-ylidene)methylpyrrole such as 14 (C(5)-OH) and 15 (C(5)-SH). CONCLUSIONS: Among newly synthetic compounds, 7 and 13-15 exhibited significant inhibitory activities against VEGFR-2 and PDGFRβ. Of these, the experimental results suggest that 15 might be a promising anti-proliferative agent. Graphical abstract IC(50) comparison of sunitinib, 14, and 15 against VEGFR-2 and PDGFRβ.