Novel Perbutyrylated Glucose Derivatives of (-)-Epigallocatechin-3-Gallate Inhibit Cancer Cells Proliferation by Decreasing Phosphorylation of the EGFR: Synthesis, Cytotoxicity, and Molecular Docking.

Ya Wang,Yun Niu,Cheng-Ting Zi,Li-Xia Wang,Xuan-Jun Wang,Ning Zhang,Fa-Wu Su,Dong-Ying Zhang,Jun Sheng,Xiao-Jing Shen,Yi-Long Wu,Yin-Rong Xie

doi:10.3390/molecules26144361

Ya Wang, Yun Niu + Show 10 more

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https://doi.org/10.3390/molecules26144361

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Journal: Molecules (Basel, Switzerland)	Publication Date: Jul 19, 2021
Citations: 7	License type: CC BY 4.0

Affiliation: Yunnan Agricultural University

Abstract

Lung cancer is one of the most commonly occurring cancer mortality worldwide. The epidermal growth factor receptor (EGFR) plays an important role in cellular functions and has become the new promising target. Natural products and their derivatives with various structures, unique biological activities, and specific selectivity have served as lead compounds for EGFR. D-glucose and EGCG were used as starting materials. A series of glucoside derivatives of EGCG (7–12) were synthesized and evaluated for their in vitro anticancer activity against five human cancer cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480. In addition, we investigated the structure-activity relationship and physicochemical property–activity relationship of EGCG derivatives. Compounds 11 and 12 showed better growth inhibition than others in four cancer cell lines (HL-60, SMMC-7721, A-549, and MCF), with IC50 values in the range of 22.90–37.87 μM. Compounds 11 and 12 decreased phosphorylation of EGFR and downstream signaling protein, which also have more hydrophobic interactions than EGCG by docking study. The most active compounds 11 and 12, both having perbutyrylated glucose residue, we found that perbutyrylation of the glucose residue leads to increased cytotoxic activity and suggested that their potential as anticancer agents for further development.

Highlights

Lung cancer is one of the most commonly occurring cancer mortality worldwide, accounting for 20% of all cancer-related deaths [1]
75–85% of lung cancers are non-small-cell lung cancer (NSCLC), including lung adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma (LCC) histological subtypes, and are typically diagnosed at advanced stages [2,3]
We synthesized a series of glucoside derivatives of EGCG (7–12) and evaluated for their in vitro anticancer activity against five human cancer cell lines, including HL-60, SMMC-7721, A-549, MCF-7, and SW480

Summary

Introduction

Lung cancer is one of the most commonly occurring cancer mortality worldwide, accounting for 20% of all cancer-related deaths [1]. The identification of key oncogenic-driver mutations has led to the development of molecular targeted therapies for patients with NSCLC [4]. The T790M mutation of EGFR has led to resistance to these EGFR TKIs [13], and new drugs have been developed, such as afatinib [10,14] and osimertinib [15]. Natural products and their derivatives with various structures, unique biological activities, and specific selectivity have served as lead compounds for EGFR. Aeroplysinin selectively inhibits EGFR [16]; shikonin preferentially inhibits cell proliferation by inhibiting EGFR-signaling [17]

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