RESUMO
A novel series of inhibitors of cancer cell proliferation, selective against p21 cell cycle checkpoint-disrupted cells vs. cells with intact p21 checkpoint, were identified by high-throughput screening. Optimization of both ends of the lead molecule to improve potency, using parallel synthesis and iterative design, is described. The 2-(1,4-dibenzodioxane)-substituted derivative 14 was identified as a highly selective and potent agent displaying an IC50 of 91 nM in the p21-deficient cell line.
Assuntos
Antineoplásicos/síntese química , Pirimidinonas/síntese química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Pirimidinonas/farmacologia , Relação Estrutura-Atividade , Tubulina (Proteína)/efeitos dos fármacosRESUMO
A novel series of PAI-1 inhibitors containing an oxadiazolidinedione moiety were identified by high through-put screening. Optimization of substituents by parallel synthesis and the iterative design toward understanding structure-activity relationship to improve potency are described.
Assuntos
Inibidor 1 de Ativador de Plasminogênio/metabolismo , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Isomerismo , Microscopia de Fluorescência , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
The ZipA-FtsZ protein-protein interaction is a potential target for antibacterial therapy. The design and parallel synthesis of a combinatorial library of small molecules, which target the FtsZ binding area on ZipA are described. Compounds were demonstrated to bind to the FtsZ binding domain of ZipA by HSQC NMR and to inhibit cell division in a cell elongation assay.