In our preliminary result, compound 1 , which contained the urea side chain and di-substituted furanopyrimidine core structure, possessed Aurora A kinase inhibition with an IC50 of 43 nM and anti-proliferation against HCT-116 with an IC50 of 400 nM. In the present work, we applied the scaffold-hopping strategy to explore the structure-activity relationship of this series of kinase inhibitors. Based on the bioisosterism, various five-member heterocyclic-fused pyrimidine cores with a variety of substitutents were synthesized to replace the furanopyrimidine moiety, such as thiopheno-, oxazolo-, imidazolo-, pyrrolo-pyrimidine and quinazoline. It is noted that the inhibitors containing thienopyrimidine or quinazoline as core structure revealed the remarkable antiproliferative activity with the low IC50 value of 21 nM and 20 nM, respectively. After introducing the solubilizing group into quinazoline core, the final compound showed significant in vivo antiproliferative activity in HCT-116 tumor xenograft model.

Design and synthesis of Aurora kinase inhibitors as anticancer agents

245th National Meeting (2013)

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