Open AccessDesign, synthesis, antitumor evaluations and molecular modeling studies of novel 3,5‐substituted indolin‐2‐one derivatives 1
Author(s) -
LI Haihong,
ZHANG Xiuhua,
TAN Jinzhi,
CHEN Lili,
LIU Hong,
LUO Xiaomin,
SHEN Xu,
LIN Liping,
CHEN Kaixian,
DING Jian,
JIANG Hualiang
Publication year - 2007
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2006.00473.x
Subject(s) - epidermal growth factor receptor , cell culture , stereochemistry , kinase insert domain receptor , tyrosine kinase , chemistry , epidermal growth factor , receptor , vascular endothelial growth factor , biochemistry , biology , cancer research , vascular endothelial growth factor a , vegf receptors , genetics
Aim: To design and synthesize a novel class of antitumor agents, featuring the 3, 5‐substituted indolin‐2‐one framework. Methods: Based on enzyme binding features of (Z)‐SU5402, introducing a β‐pyrrole group at the 3‐position of the indolin‐2‐one core, a series of novel 3,5‐substituted indolin‐2‐ones were designed and synthesized. Four human carcinoma cell lines of A‐431, A‐549, MDA‐MB‐468, and Autosomal Dominant Polycystic Kidney disease were chosen for the cell proliferation assay. Results: Twenty new compounds (1a–t) with E configuration have been designed, synthesized and bioassayed. Their structural features were determined by nuclear magnetic resonance (NMR) spectra, low‐ and high‐resolution mass spectra, and confirmed by X‐ray crystallography. Although the enzyme assay showed a weak inhibition effect against the epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet‐derived growth factor receptor tyrosine kinases, the cell‐based antitumor activity was promising. Compounds 1g and 1h showed higher inhibitory activity toward the A‐549 and MDA‐MB‐468 cell lines with IC 50 of 0.065–9.4 umol/L. Conclusion: This study provides a new template for further development of potent antitumor drugs.