1089-78-7Relevant articles and documents
Oxidation of dihydrotestosterone by human cytochromes P450 19A1 and 3A4
Cheng, Qian,Sohl, Christal D.,Yoshimoto, Francis K.,Guengerich, F. Peter
, p. 29554 - 29567,14 (2012/12/12)
Dihydrotestosterone is a more potent androgen than testosterone and plays an important role in endocrine function. We demonstrated that, like testosterone, dihydrotestosterone can be oxidized by human cytochrome P450 (P450) 19A1, the steroid aromatase. The products identified include the 19-hydroxy-and 19-oxo derivatives and the resulting Δ1,10-, Δ5,10-, and Δ9,10-dehydro 19-norsteroid products (loss of 19-methyl group). The overall catalytic efficiency of oxidation was ～10-fold higher than reported for 3α-reduction by 3α-hydroxysteroid dehydrogenase, the major enzyme known to deactivate dihydrotestosterone. These and other studies demonstrate the flexibility of P450 19A1 in removing the 1- and 2-hydrogens from 19-norsteroids, the 2-hydrogen from estrone, and (in this case) the 1-, 5β-, and 9β-hydrogens of dihydrotestosterone. Incubation of dihydrotestosterone with human liver microsomes and NADPH yielded the 18- and 19-hydroxy products plus the Δ1,10-dehydro 19-nor product identified in the P450 19A1 reaction. The 18- and 19-hydroxylation reactions were attributed to P450 3A4, and 18- and 19-hydroxydihydrotestosterone were identified in human plasma and urine samples. The change in the pucker of the A ring caused by reduction of the Δ4,5 bond is remarkable in shifting the course of hydroxylation from the 6β-, 2β-, 1β-, and 15β-methylene carbons (testosterone) to the axial methyl groups (18, 19) in dihydrotestosterone and demonstrates the sensitivity of P450 3A4, even with its large active site, to small changes in substrate structure.
11β-alkyl-Δ9-19-nortestosterone derivatives: High-affinity ligands and potent partial agonists of the androgen receptor
Muddana, Smita S.,Price, Aimee M.,MacBride, Megan M.,Peterson, Blake R.
, p. 4985 - 4988 (2007/10/03)
We report the synthesis of novel steroidal androgen receptor ligands comprising 11β-alkyl-Δ9-derivatives of 19-nortestosterone. These compounds are structurally related to the antiprogestin, antiglucocorticoid, and antiandrogen drug mifepristone (RU486). Nortestosterone analogues bearing 11β-octyl and 11β-decyl side-chains bind tightly to recombinant AR protein (IC50 = 6.6 nM and IC50 = 0.8 nM), block AR dimerization, exhibit activity against LNCaP prostate cancer cells, and comprise partial AR agonists with low antiglucocorticoid activity.
Suicide inhibitors of aromatase
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, (2008/06/13)
Thiol-substituted synthetic steriod hormones or androgens having a testosterone ring system backbone are used to inhibit aromatase''s catalyzed conversion of C 19 androgens having a A 4,3-ketone group to estrogens in the treatment of estrogen-dependent tumors, such as metastatic breast cancer in postmenopausal females.The compounds have the general formula: STR1 wherein R 1 =a thiol, such as --SH or --CH 2 SH, and R 2 =OH or =O. The preferred synthetic hormones are 17β-hydroxy-10β-mercaptoestr-4-en-3-one, 19-mercaptoandrost-4-en-3,17-dione, and 10β-mercaptoandrost-4-en-3,17-dione.
