Design, Synthesis, and Antiproliferative Evaluation of Novel Coumarin/2-Cyanoacryloyl Hybrids as Apoptosis Inducing Agents by Activation of Caspase-Dependent Pathway.

Yu-Ying Zhang,Hua Zhang,Jia-Li Song,Cheng-Shi Jiang,Liang Zhang,Qian-Qian Zhang

doi:10.3390/molecules23081972

Yu-Ying Zhang, Hua Zhang + Show 4 more

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https://doi.org/10.3390/molecules23081972

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Abstract

A series of novel coumarin/2-cyanoacryloyl hybrids were prepared and evaluated for their in vitro anticancer activity. Among them, two analogs 5p and 5q showed promising antiproliferative activity against a panel of cancer cell lines, including A549, H157, HepG2, MCF7, MG63, and U2OS. Particularly, 5q showed the most potent activity towards MG63 cells with an IC50 value of 5.06 ± 0.25 μM. Morphological observation and 4,6-diamidino-2-phenylindole (DAPI) staining assay showed that 5q-treated MG63 cells displayed significant apoptosis characteristics. Moreover, flow cytometric detection of phosphatidylserine externalization revealed that 5q induced MG63 apoptosis in a dose-dependent manner. Real-time PCR and western blot assay further confirmed that 5q had strong effects to induce MG63 cell apoptosis, suggesting that the action was associated with down-regulation of the anti-apoptotic protein Bcl-2, upregulation of pro-apoptotic protein Bax, and induced activation of caspase-3, 8, and 9. The present results provide a new chemotype for anticancer drug development and continuing investigation into candidates with coumarin/2-cyanoacryloyl scaffold is warranted.

Highlights

Cancer is one of the most leading health hazards and the prominent cause of death worldwide [1].In the past several decades, a number of anticancer drugs have been developed for the clinical treatment of various cancerous diseases, but none of them is perfectly sufficient due to the multidrug resistance and the high incidence of side effects, such as cardiotoxicity, diarrhea, and neutropenia [2,3]
Real-time PCR and western blot assay further confirmed that 5q had strong effects to induce MG63 cell apoptosis, suggesting that the action was associated with down-regulation of the anti-apoptotic protein Bcl-2, upregulation of pro-apoptotic protein Bax, and induced activation of caspase-3, 8, and 9
The present results provide a new chemotype for anticancer drug development and continuing investigation into candidates with coumarin/2-cyanoacryloyl scaffold is warranted

Summary

Introduction

In the past several decades, a number of anticancer drugs have been developed for the clinical treatment of various cancerous diseases, but none of them is perfectly sufficient due to the multidrug resistance and the high incidence of side effects, such as cardiotoxicity, diarrhea, and neutropenia [2,3]. This status makes the development of new anticancer medicines urgently necessary. Over the last thirty years, natural product-derived novel anticancer drugs have undoubtedly occupied the dominating position in drug development [4]. The promising biological profile has stimulated medicinal chemists’ great interest

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