Abstract
Casein kinase II (CK2) is an intensively studied enzyme, involved in different diseases, cancer in particular. Different scaffolds were used to develop inhibitors of this enzyme. Here, we report on the synthesis and biological evaluation of twenty phenolic, ketonic, and para-quinonic indeno[1,2-b]indole derivatives as CK2 inhibitors. The most active compounds were 5-isopropyl-1-methyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4h and 1,3-dibromo-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4w with identical IC50 values of 0.11 µM. Furthermore, the development of a QSAR model based on the structure of indeno[1,2-b]indoles was performed. This model was used to predict the activity of 25 compounds with naphtho[2,3-b]furan-4,9-dione derivatives, which were previously predicted as CK2 inhibitors via a molecular modeling approach. The activities of four naphtho[2,3-b]furan-4,9-dione derivatives were determined in vitro and one of them (N-isopentyl-2-methyl-4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-3-carboxamide) turned out to inhibit CK2 with an IC50 value of 2.33 µM. All four candidates were able to reduce the cell viability by more than 60% after 24 h of incubation using 10 µM.
Highlights
Human CK2 is an S/T protein kinase, able to phosphorylate the bovine casein in vitro
Twenty active indeno[1,2-b]indoles with IC50 values between 25 and 4100 nM were used as a training set (Table 1) to develop a reliable QSAR model
This model was challenged against a test set of ten identically active indeno[1,2-b]indole derivatives, having IC50 values between 140 and 4160 nM (Table 2)
Summary
Human CK2 (casein kinase II) is an S/T protein kinase, able to phosphorylate the bovine casein in vitro. Different CK2 inhibitors were discovered via molecular modeling approaches (QSAR, docking, database mining, etc.), such as ellagic acid and quinalizarin [23]. QSAR studies can be considered one of the main tools for drug discovery and design This approach is based on the fact that biological activities of the tested compounds can be related to their structures. For this purpose, molecular descriptors representing the molecule’s characteristics are predicted and correlated with the activity in order to develop such QSAR models. We developed a structure-based pharmacophore model using indeno[1,2-b]indoles designed and tested as CK2 inhibitors [24]. 20 indeno[1,2-b]indole derivatives were synthesized and their inhibitory activity was evaluated toward the target enzyme
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