Survivin is a nodal protein involved in several cellular pathways. It is a member of the IAP family and an integral component of the chromosomal passenger complex, where it binds to borealin and INCENP through its dimerization interface. By targeting survivin with a small molecule at its dimerization interface, inhibition of the proliferation of cancer cells has been suggested. With Abbott 8, a small-molecule dimerization inhibitor has been recently reported. The structure–activity relationship of this series of inhibitors implied that the middle pyridin-2(1 H)-one ring did not tolerate modifications of any kind.
Based on the synthetic strategy of Abbott 8 using multicomponent reactions, we synthesized a series of small molecules bearing a novel rigidized core scaffold. This rigidization strategy was accomplished by integrating the pyridin-2(1 H)-one and its 6-phenyl substituent into a tricyclic structure, linking position 5 of pyridin-2(1 H)-one to the phenyl substituent by rings of different sizes. The new scaffolds were designed based on in silico molecular dynamics of survivin.