Design, antitumor, and anti‐Ras activity of propynyl‐substituted harmine bases

Abstract

AbstractModifications at the harmine (HAM) 9‐N position demonstrated effective antitumor activity in previous studies. However, the difficult preparation, low yield and poor stability of derivatives limited their applications. A partial activity priming was carried out by converting the 9‐position substituted propargyl group of HAM to propynyl group. Molecular docking simulations of compound 9i with DYRK1A kinase showed that it was able to embed itself into the active pocket of the DYRK1A protein and formed hydrogen bonds with multiple active amino acid residues at a low binding energy. The results of molecular dynamics simulations showed that the RMSD (root mean square deviation) fluctuations of the complex were more gentle, and the trends of the changes in Rg (radius of gyration) and SASA (solvent accessible surface area) were lower, indicating that the DYRK1A protein was less disturbed and the structure of the complex was more compact and stable. The cytotoxicity assay indicated that compound 9i displayed good antiproliferative activity against human cancer cells MGC‐803, HepG2, and PANC‐1. In addition, 9i was able to reduce the ratio of polynomials induced by the Ras overexpression model of Caenorhabditis elegans, which showed anti‐Ras activity, and the RT‐qPCR results suggested that its anti‐Ras ability was not achieved by directly inhibiting the expression of the let‐60/Ras genes, and that 9i was able to upregulate the expression of SOD‐3 activation of oxidative stress, which means that it may be useful as a pro‐oxidant for the treatment of cancers caused by Ras over‐activation.