The discovery of novel sanjuanolide derivatives as chemotherapeutic agents targeting castration-resistant prostate cancer

Abstract

There remains a critical need for more effective therapies for the treatment of castration-resistant prostate cancer (CRPC), which is the leading cause of death in patients with prostate cancer. In this study, a series of sanjuanolide derivatives were designed, synthesized and evaluated as potential anti-CRPC agents. Most of the compounds had excellent selectivity for CRPC cells with IC50 values < 20 µM. Moreover, minimal side effects on human normal hepatic MIHA cells and normal prostatic stromal myofibroblast WPMY-1 cells were observed, with IC50 > 100 µM. The representative compound S07 slowed down the proliferative rate of CRPC cells, promoted cell apoptosis and caused G2/M phase accumulation, as well as G1/G0 phase reduction. Further mechanistic studies showed that S07 treatment triggered intense DNA damage and provoked strong DNA damage response in a dose-dependent manner. These findings suggested that sanjuanolide derivatives, especially S07, selectively induced CRPC cell death by triggering intense DNA damage and DNA damage response.