The Discovery Of Novel Sanjuanolide Derivatives As Chemotherapeutic Agents Targeting Castration-Resistant Prostate Cancer

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 mu M. Moreover, minimal side effects on human normal hepatic MIHA cells and normal prostatic stromal myofibroblast WPMY-1 cells were observed, with IC50 100 mu M. 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 dosedependent manner. These findings suggested that sanjuanolide derivatives, especially S07, selectively induced CRPC cell death by triggering intense DNA damage and DNA damage response.