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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
Author(s) -
Huang JiannJyh,
Lin YuHsiang,
Lai ChunLiang,
Yang ShengChuan,
Lin Shu Fu,
Yang JuYing,
Huang HungJyun,
Liu Chiawei,
Wei WinYin,
Chuang ShihHsien,
Chiang ChaoCheng,
Lee YingShuen E.,
Liao ChuBin,
Chern Ching Yuh
Publication year - 2020
Publication title -
journal of the chinese chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.329
H-Index - 45
eISSN - 2192-6549
pISSN - 0009-4536
DOI - 10.1002/jccs.201900466
Subject(s) - chemistry , kinase , potency , moiety , side chain , kinase insert domain receptor , ic50 , fibroblast growth factor receptor , stereochemistry , vegf receptors , biochemistry , fibroblast growth factor , in vitro , cancer research , receptor , vascular endothelial growth factor , vascular endothelial growth factor a , organic chemistry , biology , polymer
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‐β, 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 (IC 50 : 25–260 nM), and compound 3g with a N , N ‐dialkyl‐2‐carbamoylethyl side chain was more active for VEGFR2 (IC 50 : 59 nM) and PDGFR‐β (IC 50 : 16 nM) than FGFR‐1 (IC 50 : 1.7 μM). The C‐3′ 3‐(dialkylamino)propyl side chain accomplished 3h – j as selective PDGFR‐β inhibitors (IC 50 : 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 .