RESUMEN

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.

Asunto(s)

Antineoplásicos/síntesis química , Cisteína/metabolismo , Lactonas/síntesis química , Proteína Oncogénica v-akt/antagonistas & inhibidores , Piranos/síntesis química , Alquilación , Antineoplásicos/química , Antineoplásicos/farmacología , Biomarcadores/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Lactonas/química , Lactonas/farmacología , Naftoquinonas/síntesis química , Naftoquinonas/química , Naftoquinonas/farmacología , Piranos/química , Piranos/farmacología , Estereoisomerismo , Relación Estructura-Actividad