RESUMO
Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.
Assuntos
Imidazóis/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirazinas/química , Animais , Aurora Quinase A , Aurora Quinases , Avaliação Pré-Clínica de Medicamentos , Imidazóis/síntese química , Imidazóis/farmacocinética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Serina-Treonina Quinases/metabolismo , Pirazinas/síntese química , Pirazinas/farmacocinética , RatosRESUMO
Recently, significant attention has been focused on the synthesis small-molecule libraries based on natural product or natural product-like structures. In this paper, we report our initial studies on the use of the 1,7-dioxaspiro[5,5]undecane (spiroketal) moiety as a rigid-core template for elaboration using parallel synthesis techniques. The synthesis of a spiroketal scaffold that is reminiscent of the spiroketal subunits found in the spiroketal macrolide antibiotics will be described. Elaboration of three independently addressable functional groups on the scaffold using solution-phase parallel synthesis techniques led to the preparation of a small library of natural product-like compounds. These studies pave the way for evaluation of highly functionalized spiroketals in phenotypic assays and as prospective antagonists of protein-protein interactions.