Design, synthesis, antitumor evaluations and molecular modeling studies of novel 3,5-substituted indolin-2-one derivatives.
OBJECTIVE
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 beta-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 1 g and 1 h showed higher inhibitory activity toward the A-549 and MDA-MB-468 cell lines with IC(50 ) of 0.065-9.4 micromol/L.


CONCLUSIONS
This study provides a new template for further development of potent antitumor drugs.
Li
Hai-Hong
HH
Center for Drug Discovery and Design, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
Zheng
Xiu-Hua
XH
Tan
Jin-Zhi
JZ
Chen
Li-Li
LL
Liu
Hong
H
Luo
Xiao-Min
XM
Shen
Xu
X
Lin
Li-Ping
LP
Chen
Kai-Xian
KX
Ding
Jian
J
Jiang
Hua-Liang
HL
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D017468:Receptors, Fibroblast Growth Factor; C456900:indolin-2-one; D066246:ErbB Receptors; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor