Design, Synthesis, and Activity Assays of Cyclin-Dependent Kinase 1 Inhibitors With Flavone Scaffolds

Abstract

Cyclin-dependent kinase 1 (CDK1) plays an indispensable role in the whole cell cycle. It has become a new target for cancer therapy. According to the binding mode of a pan-CDK inhibitor, flavopiridol with CDK1, and our previous work, a new series of flavone derivatives were discovered. Among them, compound 2a showed the best CDK1 inhibitory and anti-proliferative potencies in the in vitro activity investigation. The IC50 of 2a against CDK1 was 36.42 ± 1.12 μM vs. 11.49 μM ± 0.56 of flavopiridol. In the anti-proliferation activity assays, 2a exhibited better activity toward RAW264.7 than MCF-7 cells. The results indicated that flavone derivatives, besides inhibiting the growth of tumor cells, can also antagonize inflammatory response. Molecular docking results showed that conformation of 2a can form hydrogen bonds and various hydrophobic interactions with the key amino acid residues of CDK1. It can be used as a promising lead compound for CDK1 inhibitor development.

Apoptotic and Cell Cycle Effects of Triterpenes Isolated from Phoradendron wattii on Leukemia Cell Lines

“…Molecular docking studies were performed using LeDock software [ 46 ]. A receptor grid was set for each target, restraining it to include position of co-crystalized inhibitor and surrounding cavities in accordance with previous reports for new inhibitor search [ 47 , 48 , 49 , 50 , 51 , 52 , 53 ] (resulting search volumes shown in Table 3 ), generated poses were set to 100 and 0.5 of RMSD. Generated poses and interactions were analyzed in BIOVIA Discovery Studio Visualizer v19.1.…”