Issue 28, 2022

Structure-based design and synthesis of a novel long-chain 4′′-alkyl ether derivative of EGCG as potent EGFR inhibitor: in vitro and in silico studies

Abstract

Herein, we report the discovery of a novel long-chain ether derivative of (−)-epigallocatechin-3-gallate (EGCG), a major green tea polyphenol as a potent EGFR inhibitor. A series of 4′′-alkyl EGCG derivatives have been synthesized via regio-selectively alkylating the 4′′ hydroxyl group in the D-ring of EGCG and tested for their antiproliferative activities against high (A431), moderate (HeLa), and low (MCF-7) EGFR-expressing cancer cell lines. The most potent compound, 4′′-C14 EGCG showed the lowest IC50 values across all the tested cell lines. 4′′-C14 EGCG was also found to be significantly more stable than EGCG under physiological conditions (PBS at pH 7.4). Further western blot analysis and imaging data revealed that 4′′-C14 EGCG induced cell death in A431 cells with shrunken nuclei, nuclear fragmentation, membrane blebbing, and increased population of apoptotic cells where BAX upregulation and BCLXL downregulation were observed. In addition, autophosphorylation of EGFR and its downstream signalling proteins Akt and ERK were markedly inhibited by 4′′-C14 EGCG. MD simulation and the MM/PBSA analysis disclosed the binding mode of 4′′-C14 EGCG in the ATP-binding site of EGFR kinase domain. Taken together, our findings demonstrate that 4′′-C14 EGCG can act as a promising potent EGFR inhibitor with enhanced stability.

Graphical abstract: Structure-based design and synthesis of a novel long-chain 4′′-alkyl ether derivative of EGCG as potent EGFR inhibitor: in vitro and in silico studies

Supplementary files

Article information

Article type
Paper
Submitted
24 Mar 2022
Accepted
07 Jun 2022
First published
16 Jun 2022
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2022,12, 17821-17836

Structure-based design and synthesis of a novel long-chain 4′′-alkyl ether derivative of EGCG as potent EGFR inhibitor: in vitro and in silico studies

S. Singh, R. Sahadevan, R. Roy, M. Biswas, P. Ghosh, P. Kar, A. Sonawane and S. Sadhukhan, RSC Adv., 2022, 12, 17821 DOI: 10.1039/D2RA01919A

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