新型细胞毒异喹啉醌同二聚体的制备。一种双联药物方法。

Preparation of Novel Homodimers Derived from Cytotoxic Isoquinolinequinones. A Twin Drug Approach.

机构信息

Facultad de Química y Biología, Universidad de Santiago de Chile, Alameda 3363, Casilla 40, Santiago 9170022, Chile.

Facultad de Ciencias de la Salud, Universidad Arturo Prat, Casilla 121, Iquique 1100000, Chile.

出版信息

Molecules. 2018 Feb 16;23(2):439. doi: 10.3390/molecules23020439.

DOI:10.3390/molecules23020439

PMID:29462956

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6100386/

Abstract

The synthesis of five novel homodimers is reported based on the anilinoisoquinolinequinone scaffold. In these twin-drug derivatives, two units of the anilinoquinone pharmacophores are linked through a methylene spacer. The formation of dimers was achieved by reaction of isoquinolinequinones with 4, 4'-diaminodiphenylmethane via a sequence of two oxidative amination reactions. A preliminary in vitro screening of the homodimers reveals moderate to high cytotoxic activities against MDA-MB-21 breast adenocarcinoma and B16-F10 murine metastatic melanoma cell lines. The asymmetrical homodimer stands out due to its cytotoxic potencies at submicromolar concentrations and high selectivity index (mean IC = 0.37 μM; SI = 6.97) compared to those of etoposide (mean IC = 3.67; SI = 0.32) and taxol (mean IC = 0.35; SI = 0.91) employed as reference anticancer drugs.

摘要

报道了基于苯胺异喹啉醌骨架的 5 种新型同二聚体的合成。在这些双联药物衍生物中，通过亚甲基间隔基将两个苯胺醌药效团单元连接起来。通过异喹啉醌与 4,4'-二氨基二苯甲烷的反应，经过两个氧化氨化反应序列，形成了二聚体。对同二聚体的初步体外筛选显示，它们对 MDA-MB-21 乳腺癌腺癌细胞系和 B16-F10 鼠转移性黑色素瘤细胞系具有中等至高的细胞毒性活性。不对称同二聚体由于其在亚微摩尔浓度下的细胞毒性效力和高选择性指数（平均 IC = 0.37 μM；SI = 6.97）而引人注目，与作为参考抗癌药物的依托泊苷（平均 IC = 3.67；SI = 0.32）和紫杉醇（平均 IC = 0.35；SI = 0.91）相比。