Novel methyl indolinone-6-carboxylates containing an indole moiety as angiokinase inhibitors

Mingze Qin; Ye Tian; Xiaoqing Sun; Simiao Yu; Juanjuan Xia; Ping Gong; Haotian Zhang; Yanfang Zhao

doi:10.1016/j.ejmech.2017.08.031

Novel methyl indolinone-6-carboxylates containing an indole moiety as angiokinase inhibitors

Eur J Med Chem. 2017 Oct 20:139:492-502. doi: 10.1016/j.ejmech.2017.08.031. Epub 2017 Aug 14.

Authors

Mingze Qin¹, Ye Tian¹, Xiaoqing Sun¹, Simiao Yu¹, Juanjuan Xia¹, Ping Gong¹, Haotian Zhang², Yanfang Zhao³

Affiliations

¹ Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China.
² Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: zhanghaotian2087@163.com.
³ Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: yanfangzhao@126.com.

PMID: 28826084
DOI: 10.1016/j.ejmech.2017.08.031

Abstract

A novel series of methyl indolinone-6-carboxylates bearing an indole moiety were identified as potent angiokinase inhibitors. The most active compound, A8, potently targeted the kinase activities of vascular endothelial growth factor receptors 2 and 3, and platelet-derived growth factor receptors α and β, with IC₅₀ values in the nanomolar range. In addition, A8 effectively suppressed the proliferation of human umbilical vein endothelial cells, and HT-29 and MCF-7 cancer cells, by inducing apoptosis. Compound A8 is thus a promising candidate for further investigation.

Keywords: Angiokinase inhibitors; Antitumour activity; Methyl indolinone-6-carboxylates; Ring-fused strategy.

MeSH terms

Apoptosis / drug effects
Carboxylic Acids / chemical synthesis
Carboxylic Acids / chemistry
Carboxylic Acids / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Human Umbilical Vein Endothelial Cells / drug effects
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Molecular Structure
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 1 / metabolism
Receptor, Platelet-Derived Growth Factor alpha / antagonists & inhibitors
Receptor, Platelet-Derived Growth Factor alpha / metabolism
Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
Receptor, Platelet-Derived Growth Factor beta / metabolism
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-2 / metabolism
Vascular Endothelial Growth Factor Receptor-3 / antagonists & inhibitors
Vascular Endothelial Growth Factor Receptor-3 / metabolism

Substances

Carboxylic Acids
Indoles
indolinone-6-carboxylate
FGFR1 protein, human
FLT4 protein, human
KDR protein, human
PDGFRB protein, human
Receptor, Fibroblast Growth Factor, Type 1
Receptor, Platelet-Derived Growth Factor alpha
Receptor, Platelet-Derived Growth Factor beta
Vascular Endothelial Growth Factor Receptor-2
Vascular Endothelial Growth Factor Receptor-3