RESUMO
The rational structural modification of new substituted indolizin-3-yl(phenyl)methanones 1a-i, 2a-i and 3a-i has greatly improved human farnesyltransferase inhibition. The para-bromophenyl analog 2f bearing an ester unit on the indolizine ring demonstrates the highest inhibition potential, with IC50 value of 1.3±0.2 µM. The amidic series 1a-i proves to be the most promising for future modulations, particularly at the triple bond level.
Assuntos
Inibidores Enzimáticos/química , Farnesiltranstransferase/antagonistas & inibidores , Indolizinas/química , Sítios de Ligação , Domínio Catalítico , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Farnesiltranstransferase/metabolismo , Humanos , Indolizinas/síntese química , Indolizinas/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
The biological screening of the chemical library of our Organic Chemistry Department, carried out on an automated fluorescence-based FTase assay, allowed us to discover that a phenothiazine derivative (1d) was an inhibitor of farnesyltransferase. Three new series of human farnesyltransferase inhibitors, based on a phenothiazine scaffold, were synthesized with protein farnesyltransferase inhibition potencies in the low micromolar range. Ester derivative 9d was the most active compound in these series. Four synthesized compounds were evaluated for their antiproliferative activity on a NCI-60 cancer cell line panel. The modest results obtained in this preliminary investigation showed that mixing the phenothiazine and the 1,2,3-triazole motif in the structure of a single compound can lead to new scaffolds in the field of farnesyltransferase inhibitors.
