新型3,5-取代吲哚啉-2-酮衍生物的设计、合成、抗肿瘤评估及分子模拟研究

Design, synthesis, antitumor evaluations and molecular modeling studies of novel 3,5-substituted indolin-2-one derivatives.

作者信息

Li Hai-Hong, Zheng Xiu-Hua, Tan Jin-Zhi, Chen Li-Li, Liu Hong, Luo Xiao-Min, Shen Xu, Lin Li-Ping, Chen Kai-Xian, Ding Jian, Jiang Hua-Liang

机构信息

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.

出版信息

Acta Pharmacol Sin. 2007 Jan;28(1):140-52. doi: 10.1111/j.1745-7254.2007.00473.x.

DOI:10.1111/j.1745-7254.2007.00473.x

PMID:17184594

Abstract

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 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.

CONCLUSION

This study provides a new template for further development of potent antitumor drugs.

摘要

目的

设计并合成一类新型抗肿瘤药物，其特征为具有3,5 - 二取代吲哚 - 2 - 酮骨架。

方法

基于(Z)-SU5402的酶结合特征，在吲哚 - 2 - 酮核心结构的3位引入一个β - 吡咯基团，设计并合成了一系列新型3,5 - 二取代吲哚 - 2 - 酮。选择四种人类癌细胞系A - 431、A - 549、MDA - MB - 468和常染色体显性多囊肾病细胞系进行细胞增殖测定。

结果

设计、合成并生物测定了20种具有E构型的新化合物(1a - t)。通过核磁共振(NMR)光谱、低分辨率和高分辨率质谱确定了它们的结构特征，并通过X射线晶体学得到证实。虽然酶活性测定显示对表皮生长因子受体、血管内皮生长因子受体、成纤维细胞生长因子受体和血小板衍生生长因子受体酪氨酸激酶的抑制作用较弱，但基于细胞的抗肿瘤活性很有前景。化合物1g和1h对A - 549和MDA - MB - 468细胞系显示出较高的抑制活性，IC(50)为0.065 - 9.4微摩尔/升。