RESUMO
The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.
Assuntos
Antineoplásicos/síntese química , Cisteína/metabolismo , Lactonas/síntese química , Proteína Oncogênica v-akt/antagonistas & inibidores , Piranos/síntese química , Alquilação , Antineoplásicos/química , Antineoplásicos/farmacologia , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Lactonas/química , Lactonas/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/química , Naftoquinonas/farmacologia , Piranos/química , Piranos/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Modification of alpha-biphenylsulfonamidocarboxylic acids led to potent and selective MMP-13 inhibitors. Compound 16 showed 100% oral bioavailability in rats and demonstrated >50% inhibition of bovine cartilage degradation at 10 ng/mL.