The prostate adenocarcinoma is the cancer with the highest incidence for men in Western countries. Targeting
the androgen receptor (AR) by antagonists is used as hormone therapy for prostate cancer (PCa), however, eventually
therapy resistance occurs in most patients. In most of these cancer the AR signaling is active and thus AR remains an important
drug target. Since many years we are characterizing novel chemical structural platforms to provide a broader possibility
for compounds that bind to and act as AR antagonists. Here, we describe the chemical synthesis of a battery of
novel steroidal derivatives as nor-homo-, spiro-oxolan- and spiro-oxetan- steroids. They modulate the transcriptional activity
of the human AR. As AR antagonists, the spiro-oxetan- steroid derivatives seem to be the most potent steroid derivatives.
They inhibit the transcriptional activity of both wild-type AR as well as the AR mutant T877A. In line with this,
these compounds bind to the human AR and inhibit the proliferation of the human androgen-dependent growing PCa cell
line LNCaP. Interestingly, the castration-resistant AR expressing human PC3-AR cells are also growth inhibited. On
mechanistic level, fluorescence resonance energy transfer (FRET) assays with living cells indicate that the androgeninduced
N/C terminal interaction of the AR is inhibited by the investigated compounds. Using fluorescence recovery after
photobleaching (FRAP) assays in living cells suggest a higher mobility of the AR in the cell nuclei in the presence of
spiro-oxetan- steroidal antagonists. Together, these findings suggest that spiro-oxetan- steroids are very useful as a chemical
platform for novel AR antagonists.
Keywords: Androgen receptor, antihormone, antitumor agents, prostate cancer, steroidal antiandrogens.
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