Design, Synthesis and Evaluation of N13-Substituted Evodiamine Derivatives against Human Cancer Cell Lines

Senchuan Song,Zhiyong Chen,Huacan Song,Shaoxue Li,Yanmin Huang,Yiqian Wan

doi:10.3390/molecules181215750

Abstract

Attempting to improve the anticancer activity and solubility of evodiamine in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) solutions, thirty-eight N13-substituted evodiamine derivatives were designed, synthesized and tested for antitumor activities against six kinds of human cancer cell lines, namely prostate cancer (DU-145 and PC-3), lung cancer (H460), breast cancer (MCF-7), colon cancer (HCT-5) and glioblastoma (SF-268). The solubility of these compounds in SGF and SIF solutions was evaluated, and apoptosis induced by 2-2, 2-3, 2-16 and 3-2 was determined. The results showed: (1) among all compounds examined, 2-16 showed the highest antitumor activity and a broader spectrum of activity, with IC50 values ranging from 1–2 µM; (2) their solubility was obviously improved; (3) 2-3, 2-16 and 3-2 had a significant impact inducing apoptosis in some cancer cell lines. The preliminary structure-activity relationships of these derivatives were discussed.

Highlights

Evodiamine (1, Figure 1) is a quinolone alkaloid isolated from the fruit of Evodia rutaecarpa (Chinese name: Wu-Chu-Yu), which is one of the most popular and multi-purpose Traditional ChineseMedicines widely used for treating diverse human disorders [1] and is very attractive as a component of healthy foods [2,3]
It was demonstrated by Hu [4] and Linag [1] that evodiamine possesses a wide range of biological activities related to anti-inflammatory, anti-obesity and antitumor properties
It was demonstrated that evodiamine sensitized chemoresistant breast cancer cells to adriamycin without obvious cytotoxicity against normal human peripheral blood cells [4,23], which indicated the potential of evodiamine for clinical application

Summary

Introduction

Medicines widely used for treating diverse human disorders [1] and is very attractive as a component of healthy foods [2,3] It was demonstrated by Hu [4] and Linag [1] that evodiamine possesses a wide range of biological activities related to anti-inflammatory, anti-obesity and antitumor properties. Both the strong cytotoxicity of evodiamine against human cancer cells and the underlining mechanisms of growth inhibition, apoptosis induction and suppression of invasion and metastasis have attracted much attention [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22]. Despite its promosing anticancer potential, evodiamine is still unsuitable for clinical application because of its poor physicochemical properties

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Conclusion