靶向人类雄激素受体并且作为抗雄激素的新颖的Nor-Homo- and Spiro-Oxetan- 类固醇

Title:Novel Nor-Homo- and Spiro-Oxetan- Steroids Target the Human Androgen Receptor and Act as Antiandrogens

Volume: 22 Issue: 9

Author(s): M. Thiele, S. Rabe, W. Hessenkemper, D. Roell, S. Bartsch, F. Kraft, T.E. Abraham, A.B. Houtsmuller, M.E. van Royen, A. Giannis and A. Baniahmad

Affiliation:

关键词: 雄激素受体，抗激素，抗肿瘤，前列腺癌，甾体抗雄激素。

摘要: 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.

Cite this article as:

M. Thiele, S. Rabe, W. Hessenkemper, D. Roell, S. Bartsch, F. Kraft, T.E. Abraham, A.B. Houtsmuller, M.E. van Royen, A. Giannis and A. Baniahmad , Novel Nor-Homo- and Spiro-Oxetan- Steroids Target the Human Androgen Receptor and Act as Antiandrogens, Current Medicinal Chemistry 2015; 22 (9) . https://dx.doi.org/10.2174/0929867321666140601164240