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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...

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Detalles Bibliográficos
Autores principales: Yang, Ting-Hsuan, Lee, Chun-I, Huang, Wen-Hsin, Lee, An-Rong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539068/
https://www.ncbi.nlm.nih.gov/pubmed/29086859
http://dx.doi.org/10.1186/s13065-017-0301-5
Descripción
Sumario: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. [Figure: see text] ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13065-017-0301-5) contains supplementary material, which is available to authorized users.