A New Oxopiperazin-Based Peptidomimetic Molecule Inhibits Prostatic Acid Phosphatase Secretion and Induces Prostate Cancer Cell Apoptosis

摘要

Reduced Prostatic acid Phosphatase (PAcP) secretion is asso- ciated with inhibition of the proliferation rate of prostate can- cer cells. Signal peptidase 1 (SPase 1) is the main protease that cleaves the signal peptide of secretory proteins and allows their secretion. Thus, we hypothesised that inhibition of SPase 1 might lead to an antiproliferative effect in prostate cancer cells. Using homology computer modelling, we created a hu- man SPase 1 model. With this model we designed and syn- thesised four novel (S)-3-(4-aminobutyl)piperazin-2-one-based peptidomimetics. The in vitro cytotoxic activity of these com- pounds was evaluated in the Lymph Node Carcinoma of the Prostate (LNCaP) cancer cell line. Indeed, (S)-(3-(2-(4-(((benzy- loxy)carbonyl)amino)butyl)-4-(3-methoxy-3-oxopropyl)-3-ox- opiperazin-1-yl)propyl)boronic acid, compound 8) reduced PAcP secretion, as well as exhibited significant cytotoxic effect in LNAcP cells. As reported in this study, an antiprostate cancer drug development approach, which is based on inhibiting PAcP secretion, is innovative and it might serve as source for devel- oping novel antiprostate cancer drugs.