Hauptmann, Hagen and Paulus, Birgit and Kaiser, Thomas and Herdtweck, Eberhardt and Huber, Erasmus and Luppa, Peter B. (2000) Concepts for the syntheses of biotinylated steroids. Part I: Testosterone derivatives as immunochemical probes. BIOCONJUGATE CHEMISTRY, 11 (2). pp. 239-252. ISSN 1043-1802
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We describe synthetic strategies for the biotinylation of testosterone (T) at positions 3, 7 alpha, 17 alpha, and 19. These T probes are able to mimic ligand binding and may provide for a better understanding of the biospecific interaction with steroid-binding proteins such as the androgen receptor, anti-steroid antibodies, or steroid-binding serum globulins. For the 7 alpha- and 17 alpha-derivatives, biotinyl-N-hydroxy-succinimide esters with different types of spacer chains were used. The S-biotin hydrazone derivative was produced using N-(epsilon-biotinyl)-caproyl hydrazide, whereas for the 19-biotinylation, a biotinyl-1N-diamino-3,6-dioxaoctane-amide was applied. Key reaction for the biotinylation at position 3 is the oximation of the 3-oxo function. The 17 alpha-position is accessible by the reaction of the 3-protected 4-androsten-17-epoxide with oxygen in the beta-position, followed by nucleophilic ring opening with cyanide which provides the 17 alpha-cyanomethyl derivative. The key step is the regioselective ketal protection of the 3-oxo function of androst-4-ene-3,17-dione using a stannoxane catalyst. An alternative pathway for the insertion of biotin at the 19-position was established by the synthesis of 17 beta-hydroxy-androst-4-en-3-one-19-yl carboxymethyl ether. After activation by the carbodiimide method, the compound reacts with aminoterminal biotin derivatives. The copper(I)-catalyzed 1,6 Michael addition of 17-acetoxy-6,7-dehydro-T leads to 7 alpha-derivatives by use of omega-silyl protected hydroxylalkyl-modified Grignard reagents. A functional group interconversion using the Staudinger reaction transforms the azide function into a primary omega-amino group. The absolute configurations of the different biotinylated derivatives were investigated by H-1 NMR studies. For the 7 alpha-biotinylated T series, additionally, an X-ray analysis proved the axial position of the spacer group. This,results in a vertical orientation of the biotin moiety toward the alpha-face of the planar tetracyclic backbone. Thus, a negligible alteration of the original structure of the upper beta-face offers the feasibility of applying the 7 alpha-derivatives as optimal immunochemical tracers in competitive immunoassays. Biotinylated T derivatives should be also suitable for ligand-binding studies to the androgen receptor or to sex hormone-binding globulin.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CORTICOSTEROID-BINDING GLOBULIN; COMPETITIVE CHEMILUMINESCENCE IMMUNOASSAY; CHEMI-LUMINESCENCE IMMUNOASSAY; LINKED-IMMUNOSORBENT-ASSAY; ANDROGEN RECEPTOR; STEREOSELECTIVE SYNTHESIS; SANDWICH IMMUNOASSAY; ESTRADIOL CONJUGATE; STAUDINGER REACTION; ENZYME-IMMUNOASSAY; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institut für Organische Chemie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 May 2022 12:45 |
| Last Modified: | 24 May 2022 12:45 |
| URI: | https://pred.uni-regensburg.de/id/eprint/42767 |
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