RESUMEN
In this study, we have developedsmall molecule drug conjugates (SMDCs)consisting ofa prostate specific membrane antigen (PSMA) ligandand syringolin derivatives, which are potent proteasome inhibitors, to selectively deliver syringolin derivatives to prostate cancer cells. Two parent compounds were used for syringolin derivatives with different linkage sites. These SMDCs exhibited PSMA-expressing cell-selective cytotoxicity and they could potentially be used for safer treatment of cancer.
Asunto(s)
Antígenos de Superficie , Antineoplásicos , Glutamato Carboxipeptidasa II , Inhibidores de Proteasoma , Humanos , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/síntesis química , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antígenos de Superficie/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
Development of selective or dual proteasome subunit inhibitors based on syringolin B as a scaffold is described. We focused our efforts on a structure-activity relationship study of inhibitors with various substituents at the 3-position of the macrolactam moiety of syringolin B analogue to evaluate whether this would be sufficient to confer subunit selectivity by using sets of analogues with hydrophobic, basic and acidic substituents, which were designed to target Met45, Glu53 and Arg45 embedded in the S1 subsite, respectively. The structure-activity relationship study using systematic analogues provided insight into the origin of the subunit-selective inhibitory activity. This strategy would be sufficient to confer subunit selectivity regarding ß5 and ß2 subunits.
