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

Abstract

BackgroundTumor 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 discussionThe 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).ConclusionsAmong 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 abstractIC50 comparison of sunitinib, 14, and 15 against VEGFR-2 and PDGFRβ. Electronic supplementary materialThe online version of this article (doi:10.1186/s13065-017-0301-5) contains supplementary material, which is available to authorized users.

Pyrrole indolin-2-One Based Kinase Inhibitor as Anti-Cancer Agents

“…Additionally, fusing the pyrrole moiety with five-, six-, seven-, eight-membered heterocycle (e.g., 12) specifically increases the kinase inhibitory activity and selectivity 28,29,44 . Interestingly, the smaller hetercyles (five-or six-membered heterocycle) fused pyrrole indolin-2-ones show much better VEGFR and PDGFRβ inhibitory activity 27,28,43 .…”

“…Interestingly, the smaller hetercyles (five-or six-membered heterocycle) fused pyrrole indolin-2-ones show much better VEGFR and PDGFRβ inhibitory activity 27,28,43 . Compared to sunitinib (3), the five-and six-membered heterocycle fused pyrrole indolin-2-ones demonstrate better inhibiting activity against both VEGFR-2 and PDGFRβ 28,29,44 . Among them, famitinib (n = 1, R 11 : -F in 12) showed significantly improved progression free survival (PFS) in patients with advanced colorectal cancer in phase IIb study, while its toxicity was manageable 45 .…”

“…The oxindole moiety of pyrrole indolin-2-ones can provide two hydrogen bonds, which are critical for the binding of pyrrole indolin-2-ones to the ATP-binding site of the kinases, i.e., VEGFR-2, FGFR-1, and PDK-1 4,22,23,[28][29][30][31]39,42,47 . The C(5) and C(6) positions of the pyrrole indolin-2-ons are considered as one of most effective positions for interaction with the ATP-binding site [20][21][22][23][24][25][26][27][28][29][30]48 . Since substitutions on C(5) and C(6) could substantially affect ligand protein binding affinity, these sites of the oxindole moiety are the most commonly selected for structural modification.…”

“…However, bioisosteric replacement of C(5)-halogens with C(5)-CF 3 does not improve inhibition activity against VEGFR-2 and PDGFRβ 39,41 . Linking the alkyl groups or aromatic rings with sulfonamides, amides, or a urea bond to C(5) or C( 6) is very common in the modification on the oxindole moiety 18,21,23,[27][28][29]42 . The products provide the best possible activity by enabling additional hydrogen bonding interactions.…”

“…Structureactivity relationships (SARs) of the pyrrole indolin-2-one derivatives have been comprehensively investigated in previous works [20][21][22][23][24][25][26][27][28][29][30][31] . Both the crystal data and molecular modeling data demonstrate that the C(3') amino tail of pyrrole indolin-2-one derivatives is exposed to the solvent region of the ATP-binding sites 24,[28][29][30]32,33 and has a critical influence on the solubility of the pyrrole indolin-2-one derivatives 33,34 . Additionally, the C(3') amino tail can be further modified to target the pyrrole indolin-2ones to some specific cell, organelle, or protein, such as mitochondria [35][36][37][38] .…”