The development of prostate cancer (PCa) relies strongly on the activation of the androgen receptor (AR) signaling pathway by its natural ligand dihydrotestosterone. Furthermore, PCa progression to metastatic disease represents oncogene addiction to AR activity. Androgen ablation therapy is thus a mainstay therapy against this disease, but the development of ligand-independent AR activation and persisting AR expression eventually leads to castration resistant PCa (CRPC). Therefore, down-regulation of AR expression in PCa cells may be an effective therapeutic modality. The diarylpentanoid ca27 has previously been shown to down-regulate AR expression by an unknown mechanism of action. The present work represents a preliminary structure activity relationship (SAR) study addressing the contribution of the hydroxyl (OH) groups and Michael acceptors of ca27 to the down-regulation of AR protein expression. Accordingly, LNCaP human PCa cells were treated with ca27 and a selection of analogs differing with respect to the position of the OH groups and the presence/absence of the Michael acceptors. AR expression was determined by Western blotting using specific antibodies against the AR and β-actin as a loading control and quantified using Image J analysis. The dose-dependent effect of ca27 and its analogs was visualized by bright field light microscopy. Our data shows that the presence of OH groups and Michael acceptors are major contributors of AR down-regulation. In addition, this observation was confirmed by the dose-responsive nature of our results. Our studies aim at identifying active pharmacophores of diarylpentanoids that down-regulate AR expression. When targeted to prostate cancer cells, this could lead to the development of novel therapeutics against CRPC