Abstract
Development of resistance to standard therapies complicates treatment of advanced prostate cancer. Alternative splicing variants of the androgen receptor (AR), e.g. AR-V7 can mediate resistance to AR-targeting substances abiraterone and enzalutamide. Semi-synthetic marine natural compound rhizochalinin decreases the expression of AR-V7 in human castration-resistant prostate cancer cells and thus resensitizes cells to enzalutamide.In the current study, we modified the structure of rhizochalin in order to determine structure-activity relationships (SAR) and optimize anticancer properties. Thus, we synthesized new 18-hydroxy- and 18-aminorhizochalins and its aglycones. All compounds exhibited anticancer properties in human castration-resistant prostate cancer cells, induced apoptosis and G2/M cell cycle arrest, and were capable of autophagy inhibition. SAR analysis showed an increase of pro-apoptotic activity in the row 18-amino < 18-hydroxy < 18-keto derivatives. In general, aglycones were more cytotoxic compared to glycosides. The sugar elimination was critical for the ability to suppress AR-signaling. Rhizochalinin (2) and 18-hydroxyrhizochalinin (4) were identified as the most promising derivatives and are promoted for further development.
Highlights
Androgen receptor (AR) signaling is crucial for the growth and development of normal and malignant prostate cells
All compounds were purified by reversed-phase flash column chromatography or reversed-phase HPLC and elucidated by spectroscopic methods as follows: 18-Hydroxyrhizochalin (3)
Aglycones were distinctly more active when compared with glycosides
Summary
Androgen receptor (AR) signaling is crucial for the growth and development of normal and malignant prostate cells. Androgen deprivation therapy (ADT) with GnRH agonists and antagonists is an essential step in prostate cancer treatment [1]. ADT eventually fails twelve to eighteen months after treatment initiation leading to the development of castration-resistant prostate cancer (CRPC) [1]. Second generation AR-targeting drugs enzalutamide and abiraterone are approved for the treatment of metastatic CRPC before and after chemotherapy with docetaxel. Response to the second AR-targeted drug in CRPC is decreased and a decline of progression-free survival has been reported with each additional treatment line [4]
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