Discovery of Novel and Potent Thiazoloquinazolines as Selective Aurora A and B Kinase Inhibitors

Abstract

The synthesis of a novel series of quinazolines substituted at C4 by five-membered ring aminoheterocycles is reported. Their in vitro structure-activity relationships versus Aurora A and B serine-threonine kinases is discussed. Our results demonstrate that quinazolines with a substituted aminothiazole at C4 possess potent Aurora A and B inhibitory activity and excellent selectivity against a panel of various serine-threonine and tyrosine kinases, as exemplified by compound 46. We found also that the position and nature of the substituent on the thiazole play key roles in cellular potency. Compounds with an acetanilide substituent at C5' have the greatest cellular activity. The importance of the C5' position for substitution has been rationalized by ab initio molecular orbital calculations. Results show that the planar conformation with the sulfur of the thiazole next to the quinazoline N-3 is strongly favored over the other possible planar conformation. Compound 46 is a potent suppressor of the expression of phospho-histone H3 in tumor cells in vitro as well as in vivo, where 46, administered as its phosphate prodrug 54, suppresses the expression of phospho-histone H3 in subcutaneously implanted tumors in nude mice.

Structural studies of B-type Aurora kinase inhibitors using computational methods

“…A series of 48 quinazoline derivatives with their inhibitory activities was retrieved from the literature [24,32] . We have considered only the IC 50 value for the cell-based assay (not an enzyme-based assay), which is the inhibition of histone H3 in SW620 cells.…”

“…The 3D-QSAR models were developed using the Comparative [24,32] . The structures A and B correspond to Figure 1 …”

“…It has been shown in the literature that these computational techniques can strongly support and aid in the design of novel, more potent inhibitors by revealing the mechanics of the drug-receptor interactions [29][30][31] . To explore the further possibilities of novel drugs, we have developed predictive 3D-QSAR models using quinazoline-based Aurora B inhibitors [24,32] .…”

A Novel Aminothiazole Derivative Induces Apoptosis and Cell Cycle Arrest in Tumor Cells

“…1 In the course of searching for anticancer agents, we became interested in the discovery of potential anticancer agents using a cell-based high-throughput screening system with a chemical library. We reported a preparation of 2-aminothiazole derivatives [2][3][4][5][6] in a high-speed parallel format and found that compound H154 exhibited significant cell growth inhibition against HepG2 cells with an IC 50 value of 0.040 μM by the MTT assay. 7 Apoptosis is important, not only for the chemotherapy of cancer cells, but also in tumor chemoresistance involving an increased threshold for cell death that would require higher doses to destroy the tumor.…”

“…[2][3][4][5][6] It was suggested that Cdk2 controls the G 1 /S transition in mammalian cells. However, this compound resulted in no change in the level of Cdk2 expression and did not have an inhibitory efficacy for several kinases in addition to Cdk2 (data not shown).…”