Semi-Synthesis and In Vitro Anti-Cancer Evaluation of Magnolol Derivatives.

Cheng-Zhu Wu,Hong-Mei Li,Xiao-Long Sun,Mei-Lin Zhu,Chang-Hao Zhang,Yi-Qun Dai,Bo-Han Li,Hui Ma

doi:10.3390/molecules26144302

Cheng-Zhu Wu, Hong-Mei Li + Show 6 more

Open Access

https://doi.org/10.3390/molecules26144302

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Abstract

Magnolol (MAG), a biphenolic neolignan, has various biological activities including antitumor effects. In this study, 15 MAG derivatives were semi-synthesized and evaluated for their in vitro anticancer activities. From these derivatives, compound 6a exhibited the best cytotoxic activity against four human cancer cell lines, with IC50 values ranging from 20.43 to 28.27 μM. Wound-healing and transwell assays showed that compound 6a significantly inhibited the migration and invasion of MDA-MB-231 cells. In addition, Western blotting experiments, performed using various concentrations of 6a, demonstrated that it downregulates the expression of HIF-1α, MMP-2, and MMP-9 in a concentration-dependent manner. Overall, these results suggest that substituting a benzyl group having F atoms substituted at the C2 position on MAG is a viable strategy for the structural optimization of MAG derivatives as anticancer agents.

Highlights

Triple-negative breast cancer (TNBC) is defined by a lack of expression of the estrogen receptor, epidermal growth factor receptor-2, and progesterone receptor-2
Suppressed Migration and Invasion of MDA-MB-231 Cells by Compound 6a Tumor invasion and metastasis are the causes of poor prognosis and survival in patients with breast cancer [25,26]
A series of magnolol derivatives 1a–9a and 1b–6b were semisynthesized by Williamson reaction and evaluated for their in vitro antiproliferative activity by MTT assay on four different human cancer cell lines (MDA-MB-231, MCF-7, CNE-2Z, and SMMC-7721)

Summary

Introduction

Triple-negative breast cancer (TNBC) is defined by a lack of expression of the estrogen receptor, epidermal growth factor receptor-2, and progesterone receptor-2. Natural products have many advantages, such as low toxicity and side effects, multiple targets, and reversal of cancer-drug resistance [4,5]. Natural products can have many advantages over chemotherapy, such as low toxicity, low side effects, multiple targets, and reversal of resistance to cancer drugs. Previous studies have shown that a series of MAG derivatives showed better cytotoxic activity than MAG itself [18,19,20,21,22]. These results indicated that free phenolic hydroxyl groups and hydrophobic side chains are the necessary active groups for magnolol to exert. Compound 3a, which does not bear any substitution on the benzene ring, showed good cytotoxic activity against MDA-MB-231 cells

Preliminary Screening of the Inhibitory Effect on MDA-MB-231 Cell Migration

Anti-Proliferative Activity of Compound 6a in MDA-MB-231 Cells

Suppressed Migration and Invasion of MDA-MB-231 Cells by Compound 6a

General Procedure for the Preparation of 1a–9a and 1b–6b

MTT Assay

Cell Migration Assay

Cell Invasion Assay

Findings

Conclusions