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

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. Cancer is ranked second globally as cause of death. The disease originated due to the inability of cells to control growth, often leading to the formation of cancerous tumors or liquid cancer. (i.e. leukemia and lymphoma cancer). Routines for cancer treatment consist of chemotherapy and radiotherapy where the former utilizes molecule-size drugs aiming at eradication and inhibition of cancer tumors. However, this treatment technique has been shown to suffer from several inherent shortcomings including the development of drug resistance, off-target toxicity and limited targeting capabilities 1,2. Glycogen synthase kinase-3 (GSK-3) is defined as a multifunctional serine/threonine protein kinase that regulates the phosphorylation of various cellular targets 3. The function of GSK-3 is essential for the development

Binding of Inhibitors to the Monomeric and Dimeric SARS-CoV-2 Mpro

“…However, it should be noted that the dynamics of receptors were not considered in docking simulations, and the number of trial docking poses was small. To overcome this limitation we have performed MD simulations which serve as a validation for the docking results [38][39][40] . Moreover, FPL is an efficient computational approach to assess ligand-binding affinity with a suitable time-consuming calculation.…”

Testing the effectiveness of the designing and applying process with certain circumstances in geometry teaching

“…According to many experts, exploring the ways in which high school math teachers bring new meaning to the development of general education (Widiawati et al, 2020;Valoyes Chávez, 2019;Hau et al, 2020). Following the previous theoretical examinations, ; Dan et al (2020), we propose the step-by-step process below:…”

“…In terms of a case-based learning approach, learners actively connect the study contents with the daily life context. Thus, this method could improve a better understanding of the mean for learning math (Dan et al, 2020). On the basis of students' ability to apply knowledge to real situations, we want to test the effectiveness of the process of designing and applying geometry teaching (Gutiérrez-Rubio et al, 2020;Matiash & Mykhailenko, 2020;.…”

Identification of Cytotoxic Constituents from the Whole Plant of Isodon ternifolius

“…Five isolated compounds (1, 5) were tested for their cytotoxic activity against A549, HepG2, and MDA-MB-231 cancer cell lines in vitro assay by the method as described previously. 15,16 Among them, a new compound (isodonspiroketone, 1) showed moderate cytotoxic activities against A549, HepG2, and MDA-MB-231 cancer cell lines with half-maximal inhibitory concentration (IC 50 ) values of 23.84 ± 2.73, 27.77 ± 3.01, and 17.26 ± 1.61 µM, respectively; meanwhile, the others were inactive (Table 2). In this assay, ellipticine was used as a positive control.…”

“…Ellipticine exhibited cytotoxic activity against A549, HepG2, and MDA-MB-231 cancer cell lines with IC 50 values of 1.67 ± 0.20, 2.11 ± 0.20, and 1.83 ± 0.12 µM, respectively. [15][16][17] H-NMR (400 MHz) and 13 C-NMR (100 MHz) were measured on a Varian Unity Inova 500 MHz spectrometer. TOF-MS was obtained from a Varian Fourier transform mass spectrometer and MicroQ-TOF III (Bruker Daltonics, Ettlingen Germany).…”