RESUMO
A multi-component reaction strategy was used for the fast and efficient synthesis of amide isosteres of known Bcl-2 inhibitors capable of disrupting protein-protein interactions. Ugi reaction and a subsequent nucleophilic aromatic substitution reaction provide a versatile path to libraries of compounds similar to Abbott's acylsulfonamides. Modeling arguments are used to explain the inferior activity of the amide as opposed to the sulfonamide series.
Assuntos
Proteína bcl-X/antagonistas & inibidores , Amidas/química , Apoptose , Química Farmacêutica/métodos , Cianetos/química , Desenho de Fármacos , Humanos , Modelos Químicos , Modelos Moleculares , Conformação Molecular , Neoplasias/metabolismo , Peptídeos/química , Proteínas/química , Relação Estrutura-Atividade , Sulfonamidas/química , Proteína bcl-X/químicaRESUMO
A terphenyl alpha-helix mimetic scaffold recognized to be capable of disrupting protein-protein interactions was structurally morphed into an easily amenable and versatile multicomponent reaction (MCR) backbone. The design, modular in-parallel library synthesis, initial cell based biological data, and preliminary in vitro screening for the disruption of the Bcl-w/Bak protein-protein interaction by representatives of the MCR derived scaffold are presented.
Assuntos
Materiais Biomiméticos/química , Desenho de Fármacos , Imidazóis , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/química , Proteínas , Proteína Killer-Antagonista Homóloga a bcl-2 , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Células HL-60/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Modelos Moleculares , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Mapeamento de Interação de Proteínas , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Relação Estrutura-Atividade , Proteína Killer-Antagonista Homóloga a bcl-2/antagonistas & inibidores , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/metabolismoRESUMO
A genetic algorithm (GA), driven by experimentally determined biological activities as a feedback fitness function, was used to propose novel small molecules as inhibitors of glucose-6-phosphate translocase (G6PT) in iterative rounds of evolutionary optimization. A straightforward polymer-supported synthetic sequence was implemented to synthesize molecules proposed by the GA, and the biological activities of the compounds were determined by a microsomal assay. Additional compound design strategies were integrated, such as Tanimoto similarity-based selection of starting materials and transfer of favored structure elements into a new chemical scaffold to identify more active and selective inhibitors.
Assuntos
Antiporters/antagonistas & inibidores , Diabetes Mellitus Tipo 2/enzimologia , Inibidores Enzimáticos/síntese química , Glucose-6-Fosfatase/antagonistas & inibidores , Hipoglicemiantes/síntese química , Proteínas de Transporte de Monossacarídeos/antagonistas & inibidores , Animais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glucose/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Estrutura Molecular , RatosRESUMO
Using a newly developed multicomponent chemistry strategy in combination with structure based drug design, a new class of HIV-1 protease inhibitors has been obtained.
