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Identification of substituted 5-membered heterocyclic compounds as potential anti-leukemic agents.
Eur J Med Chem ; 164: 391-398, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30611980
Although pediatric leukemia is generally treatable, certain leukemic subtypes face poor prognosis in the clinic suggesting new selective therapeutic agents are needed. Thus, to identify selective apoptosis inducers, a small-molecule library screening approach was conducted using an isogenic leukemic murine p185+ B-ALL cell line pair (BCR-ABL-WT and the BAX/BAK deficient BCR-ABL-DKO). Gratifyingly, the investigation revealed several compounds featuring substituted aromatic five-membered-ring heterocycles with significant activity against murine and human leukemic cellular models. The identified compounds represent potentially novel antileukemic molecular scaffolds exemplified by compounds 1, 2 and 7, which demonstrated EC50 values in the nanomolar and low micromolar range against various leukemia subtypes (SUP-B15, KOPN-8, NALM-06, UoC-B1 cellular models) and pro-apoptotic properties in solid tumor cell models (MDA-MB-231, SUM149) with ample therapeutic index in normal cells. Herein, we highlight compounds 1, 2 and 7 which promote cell death mediated by caspase 3/7 induction. Our study establishes a strategic platform for the development of potent and selective anti-leukemic agents.





Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Leucemia / Compostos Heterocíclicos / Antineoplásicos Aspecto clínico: Prognóstico / Terapia Limite: Animais / Humanos Idioma: Inglês Revista: Eur J Med Chem Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: Estados Unidos