title: Syntheses and ligand-binding studies of 1 alpha- and 17 alpha-aminoalkyl dihydrotestosterone derivatives to human sex hormone-binding globulin.
abstract: We report on the syntheses of 1 alpha- and 17 alpha-aminoalkyl dihydrotestosterone (DHT) derivatives and the particularly high binding affinity of the 1 alpha-aminohexyl ligand for human sex hormone-binding globulin (SHBG). The two 17 alpha-aminopropyl-17 beta-hydroxy-5 alpha-androstan-3-one (1) and 17 alpha-aminocaproylamidoethyl-17 beta-hydroxy-5 alpha-androstan-3-one (2) derivatives were synthesized via a 17beta-spirooxirane intermediate in high yields. The 1 alpha-aminohexyl-17 beta-hydroxy-5 alpha-androstan-3-one compound (3) was obtained in a seven step synthesis using a copper-catalyzed conjugate addition of a omega-silyloxyhexyl Grignard reagent to 17 beta-benzoyloxy-5 alpha-androst-1-en-3-one. All structures were elucidated based on 1H NMR spectroscopy and mass spectral analyses. The three aminosteroid derivatives were tested as ligands for SHBG by competition experiments with tritiated testosterone as tracer under equilibrium conditions. The association constants of the two 17 alpha-DHT derivatives were approximately 1 x 10(7) M(-1), whereas the 1 alpha-DHT derivative showed a remarkably high binding affinity to SHBG with an association constant of 1.40 x 10(9) M(-1). These aminoalkyl derivatives, substituted either at the D-ring or the A-ring of the steroid skeleton, can be easily coupled onto a carboxymethylated solid state surface of a biosensor. Such a device lends itself to kinetic and thermodynamic studies aimed to provide a better understanding of the biospecific interaction of steroids with SHBG.
authors.affiliation: Institute of Organic Chemistry, Universität Regensburg, Universitätsstr. 31, D-93053 Regensburg, Germany.
authors.forename: Hagen
authors.initials: H
authors.lastname: Hauptmann
authors.forename: Jochen
authors.initials: J
authors.lastname: Metzger
authors.forename: Andreas
authors.initials: A
authors.lastname: Schnitzbauer
authors.forename: Claude Y
authors.initials: CY
authors.lastname: Cuilleron
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mappus
authors.forename: Peter B
authors.initials: PB
authors.lastname: Luppa
mesh_terms: D000588:Amines; D015374:Biosensing Techniques; D013196:Dihydrotestosterone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D011485:Protein Binding; D011869:Radioligand Assay; D012738:Sex Hormone-Binding Globulin / Q000302:isolation & purification / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D008024:Ligands; D012738:Sex Hormone-Binding Globulin; D013196:Dihydrotestosterone