RESUMO
Based on NCI8642, a series of gallocyanine derivatives was synthesized with modifications of the substituent groups in position 1, 2 and 4 of the phenoxazinone scaffold. The effectiveness of gallocyanines to inhibit DKK1/LRP6 interactions and Tau phosphorylation induced by prostaglandin J2 and DKK1 was elucidated by both experimental data and molecular docking simulations. Bis-alkylated with flexible alkyl ester groups on C1 and bis-benzyl gallocyanines provided the most active inhibitors, while amino derivatives on C2 of NCI8642 that have alkoxy or benzyloxy substituents on C4, were less active. Furthermore, it is shown that treating of SHSY5Y cells with NCI8642 derivatives activates Wnt signaling and increases the levels of pGSK3ß kinase and ß-catenin.
Assuntos
Desenho de Fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Oxazinas/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Humanos , Ligação de Hidrogênio , Peptídeos e Proteínas de Sinalização Intercelular/química , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/antagonistas & inibidores , Simulação de Acoplamento Molecular , Oxazinas/farmacologia , Oxazinas/uso terapêutico , Fosforilação/efeitos dos fármacos , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Relação Estrutura-Atividade , Via de Sinalização Wnt/efeitos dos fármacos , Proteínas tau/metabolismoRESUMO
Amino derivatives of NCI8642 were synthesized and evaluated as inhibitors of DKK1/LRP6 interactions. The new inhibitors were able to activate the Wnt signaling pathway as indicated by the increased levels of ß-catenin, and decrease the DKK1-induced Tau phosphorylation at serine 396.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Oxazinas/química , Oxazinas/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Células HEK293 , Humanos , Modelos Moleculares , Oxazinas/síntese química , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Relação Estrutura-Atividade , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMO
In search of safe and effective anti-Alzheimer disease agents a series of gallocyanine dyes have been synthesized and evaluated for their ability to inhibit LRPs/DKK1 interactions. Modulation of the interactions between LRPS and DKK1, regulate Wnt signaling pathway and affect Tau phosphorylation. The current efforts resulted in the identification of potent DKK1 inhibitors which are able to inhibit prostaglandin J2-induced tau phosphorylation at serine 396.