Design, synthesis, structure, in vitro cytotoxic activity evaluation and docking studies on target enzyme GSK-3\u03b2 of new indirubin-3\u02b9-oxime derivatives

Nguyen Trong Dan,Luu Van Chinh,Tran Quoc Toan,Nguyen Manh Cuong,Ngo Thi Lan,Nguyen Huu Thuan Anh,Long Giang Bach,To Dao Cuong,Vuong Van Truong,Hoang Duc Quang,Nguyen Thi Mai,Pham Minh Quan,Do Huu Nghi

doi:10.1038/s41598-020-68134-8

Abstract

The addition of chalcone and amine components into indirubin-3′-oxime resulted in 15 new derivatives with high yields. Structures of new derivatives were also elucidated through 1D, 2D-NMR and HR-MS(ESI) spectra and X-ray crystallography. All designed compounds were screened for cytotoxic activity against four human cancer cell lines (HepG2, LU-1, SW480 and HL-60) and one human normal kidney cell line (HEK-293). Compound 6f exhibited the most marked cytotoxicity meanwhile cytotoxicity of compounds 6e, 6h and 6l was more profound toward cancer cell lines than toward normal cell. These new derivatives were further analyzed via molecular docking studies on GSK-3β enzyme. Docking analysis shows that most of the derivatives exhibited potential inhibition activity against GSK-3β with characteristic interacting residues in the binding site. The fast pulling of ligand scheme was then employed to refine the binding affinity and mechanism between ligands and GSK-3β enzyme. The computational results are expected to contribute to predicting enzyme target of the trial inhibitors and their possible interaction, from which the design of new cytotoxic agents could be created in the future.

Highlights

The addition of chalcone and amine components into indirubin-3′-oxime resulted in 15 new derivatives with high yields
GSK-3β was recognized to play a significant role in the Wingless (Wnt) signaling pathway, suggesting that the inhibition of GSK-3β could lead to decreased cancer cell proliferation, triggering the p53-dependent apoptosis and stimulate the TRAIL-induced cell death[7]
We have described an efficient pathway for the synthesis of novel indirubin-3′-oxime derivatives with advantages of simple operation conditions and high yields

Summary

Introduction

The addition of chalcone and amine components into indirubin-3′-oxime resulted in 15 new derivatives with high yields. Compound 6f exhibited the most marked cytotoxicity cytotoxicity of compounds 6e, 6h and 6l was more profound toward cancer cell lines than toward normal cell. These new derivatives were further analyzed via molecular docking studies on GSK-3β enzyme. Docking analysis shows that most of the derivatives exhibited potential inhibition activity against GSK-3β with characteristic interacting residues in the binding site. Routines for cancer treatment consist of chemotherapy and radiotherapy where the former utilizes molecule-size drugs aiming at eradication and inhibition of cancer tumors This treatment technique has been shown to suffer from several inherent shortcomings including the development of drug resistance, off-target toxicity and limited targeting c apabilities[1,2]. Recent studies on interactions between indirubin-3′-oxime with the active site of GSK-3β (PDB ID: 1Q41) offered crucial insights into intermolecular interactions and the mechanism of specificity towards this kinase[11]

Methods

Results

Conclusion