RESUMO
A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1H-pyrazol-4-yl substituent on the top and bottom of the aryl regions to produce 22 and 33, exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, 33 demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8+ T-cells, and helper CD4+ T-cells in the spleen. These findings underscored the bifunctional capabilities of 33 (BPR5K230) with excellent oral bioavailability (F = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.
Assuntos
Antineoplásicos , Receptor Tirosina Quinase Axl , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas , Receptores Proteína Tirosina Quinases , Microambiente Tumoral , c-Mer Tirosina Quinase , Animais , Microambiente Tumoral/efeitos dos fármacos , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/síntese química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Antineoplásicos/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/metabolismo , c-Mer Tirosina Quinase/antagonistas & inibidores , c-Mer Tirosina Quinase/metabolismo , Camundongos , Linhagem Celular Tumoral , Relação Estrutura-Atividade , Descoberta de Drogas , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/síntese química , Feminino , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , Proliferação de Células/efeitos dos fármacosRESUMO
An acyl radical reaction of bicyclo[2.2.2]octenone to yield either rearranged or cyclized isotwistane products is described. The influence of ring strain on the reaction was demonstrated by alternating the sizes of the fused ring in the starting material. DFT calculations showed that the reaction is under thermodynamic control and proceeds via a 5-exo-trig cyclization intermediate, which undergoes either hydrogen-atom transfer (HAT) to give a cyclized product or rearrangement via a twistane intermediate to give a rearranged product.