title: 20-Aminosteroids as a novel class of selective and complete androgen receptor antagonists and inhibitors of prostate cancer cell growth.
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.
authors.affiliation: Institut für Organische Chemie, Fakultät für Chemie und Mineralogie, Universität Leipzig, Johannisallee 29, Leipzig 04103, Germany.
authors.forename: Manolis A
authors.initials: MA
authors.lastname: Fousteris
authors.forename: Undine
authors.initials: U
authors.lastname: Schubert
authors.forename: Daniela
authors.initials: D
authors.lastname: Roell
authors.forename: Julia
authors.initials: J
authors.lastname: Roediger
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Bailis
authors.forename: Sotiris S
authors.initials: SS
authors.lastname: Nikolaropoulos
authors.forename: Aria
authors.initials: A
authors.lastname: Baniahmad
authors.forename: Athanassios
authors.initials: A
authors.lastname: Giannis
mesh_terms: D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008297:Male; D008968:Molecular Conformation; D009154:Mutation; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors / Q000235:genetics; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013237:Stereoisomerism; D013256:Steroids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D011944:Receptors, Androgen; D013256:Steroids; D017430:Prostate-Specific Antigen