A Series of New Ligustrazine-Triterpenes Derivatives as Anti-Tumor Agents: Design, Synthesis, and Biological Evaluation.

Bing Xu,Qiang Li,Yuzhong Zhang,Jing Chen,Fuhao Chu,Xiaobo Wang,Xin Xu,Haimin Lei,Penglong Wang,Wei Liu,Yanyi Xing

doi:10.3390/ijms160921035

Abstract

A series of novel ligustrazine-triterpenes derivatives was designed, synthesized and screened for their cytotoxicity against five cancer cell lines (Bel-7402, HepG2, HT-29, Hela, and MCF-7) and Madin-Darby canine kidney (MDCK). Current study suggested that most of the ligustrazine-triterpenes conjunctions showed better cytotoxicity than the starting materials. In particular, compound 4a exhibited better cytotoxic activity (IC50 < 5.23 μM) against Bel-7402, HT-29, MCF-7, Hela, and HepG2 than the standard anticancer drug cisplatin (DDP). The cytotoxicity selectivity detection revealed that 4a exhibited low cytotoxicity (IC50 > 20 μM) towards MDCK cells. A combination of fluorescence staining observation and flow cytometric analysis indicated that 4a could induce HepG2 cell apoptosis. Further studies suggested that 4a-induced apoptosis is mediated through depolarization of the mitochondrial membrane potential and increase of intracellular free Ca2+ concentration. In addition, the structure-activity relationships of these derivatives were briefly discussed.

Highlights

Natural products play a highly significant role in the development process of drug discovery [1].This was evident in the areas of anti-cancer drugs; over 60% of FDA approved anti-tumor drugs were shown to be of natural origin, such as the best known anticancer drugs vinblastine, etoposide and paclitaxel [2]
All the designed derivatives were synthesized via the routes outlined in Schemes 1 and 2
When IC50 > 20.0 μM, we considered the antiproliferative activities of the compounds were too weak to do further research; b “ND” not determined, due to the weak cytotoxicity, IC50 value of compounds on Madin-Darby canine kidney (MDCK) cells was not be detected; c “NC” means the ClogP value was not calculated

Summary

Introduction

Natural products play a highly significant role in the development process of drug discovery [1]. This was evident in the areas of anti-cancer drugs; over 60% of FDA approved anti-tumor drugs were shown to be of natural origin, such as the best known anticancer drugs vinblastine, etoposide and paclitaxel [2]. In our previous work of this field, we had designed and synthesized a series of ligustrazine-triterpenes derivatives, among which some compounds showed promising selective cytotoxicity on human carcinoma cells. It revealed that the introduction of ligustrazine could increase the cytotoxicity and selectivity of these compounds [17,20]

Methods

Results

Conclusion