20-Aminosteroids as a novel class of selective and complete androgen receptor antagonists and inhibitors of prostate cancer cell growth

Manolis A Fousteris; Undine Schubert; Daniela Roell; Julia Roediger; Nikolaos Bailis; Sotiris S Nikolaropoulos; Aria Baniahmad; Athanassios Giannis

doi:10.1016/j.bmc.2010.08.029

20-Aminosteroids as a novel class of selective and complete androgen receptor antagonists and inhibitors of prostate cancer cell growth

Bioorg Med Chem. 2010 Oct 1;18(19):6960-9. doi: 10.1016/j.bmc.2010.08.029. Epub 2010 Aug 19.

Authors

Manolis A Fousteris¹, Undine Schubert, Daniela Roell, Julia Roediger, Nikolaos Bailis, Sotiris S Nikolaropoulos, Aria Baniahmad, Athanassios Giannis

Affiliation

¹ Institut für Organische Chemie, Fakultät für Chemie und Mineralogie, Universität Leipzig, Johannisallee 29, Leipzig 04103, Germany.

PMID: 20826091
DOI: 10.1016/j.bmc.2010.08.029

Abstract

Here, the synthesis and the evaluation of novel 20-aminosteroids on androgen receptor (AR) activity is reported. Compounds 11 and 18 of the series inhibit both the wild type and the T877A mutant AR-mediated transactivation indicating AR antagonistic function. Interestingly, minor structural changes such as stereoisomers of the amino lactame moiety exhibit preferences for antagonism among wild type and mutant AR. Other tested nuclear receptors are only weakly or not affected. In line with this, the prostate cancer cell growth of androgen-dependent but not of cancer cells lacking expression of the AR is inhibited. Further, the expression of the prostate specific antigen used as a diagnostic marker is also repressed. Finally steroid 18 enhances cellular senescence that might explain in part the growth inhibition mediated by this derivative. Steroids 11 and 18 are the first steroids that act as complete AR antagonists and exhibit AR specificity.

MeSH terms

Androgen Receptor Antagonists / chemical synthesis
Androgen Receptor Antagonists / chemistry
Androgen Receptor Antagonists / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Biomarkers, Tumor / antagonists & inhibitors
Biomarkers, Tumor / genetics
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Humans
Male
Molecular Conformation
Mutation
Prostate-Specific Antigen / antagonists & inhibitors
Prostate-Specific Antigen / genetics
Prostatic Neoplasms / diagnosis
Prostatic Neoplasms / drug therapy*
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology*
RNA, Messenger / antagonists & inhibitors
RNA, Messenger / genetics
Receptors, Androgen / genetics*
Reverse Transcriptase Polymerase Chain Reaction
Stereoisomerism
Steroids / chemical synthesis
Steroids / chemistry
Steroids / pharmacology*
Structure-Activity Relationship

Substances

Androgen Receptor Antagonists
Antineoplastic Agents
Biomarkers, Tumor
RNA, Messenger
Receptors, Androgen
Steroids
Prostate-Specific Antigen