1852-53-5Relevant academic research and scientific papers
Regio- And Stereo-chemical Effects in the Hydroboration of Δ2-Steroidal Allylic and Homoallylic Alcohols
Hanson, James R.,Liman, Mansur D.,Nagaratnam, Sivajini
, p. 282 - 283 (1997)
A comparison between the hydroboration of δ2-steroidal 1x-allylic and 5x-homoallylic alcohols reveals that whereas both have a stereochemical directing effect, only the allylic alcohol modifies the regiospecificity of the reaction.
Estradiol-17β inhibition of androgen uptake, metabolism and binding in epididymis of adult male rats in vivo: A comparison with cyproterone acetate
Tindall,French,Nayfeh
, p. 257 - 268 (1981)
The effects of estradiol-17β on androgen uptake, metabolism and binding were studied in rat epididymis in vivo in comparison with cyproterone acetate. Steroids (250 ug/100 g body weight) were injected 5 min prior to 3H-testosterone in castrate rats. Estradiol-17 β inhibited 3H-testosterone uptake into epididymal cytosol by 58% as compared to 38% by cyproterone acetate. 3H-Testosterone uptake into epididymal nuclei was inhibited 95% by estradiol-17 β and 83% by cyproterone acetate. Total bound radioactivity in cytosol fractions was reduced to a greater extent by estradiol-17 β than cyproterone acetate when either 3H-testosterone or 3H-dihydrotestosterone was injected. Binding of 3H-dihydrotestosterone to nuclear receptors was completely abolished by estradiol-17 β ; whereas approximately 20% binding remained in the nuclear extract after cyproterone acetate treatment. Metabolism of 3H-testosterone in vivo was also altered by estradiol-17 β, resulting in diminished conversion to 3H-dihydrotestosterone. Cyproterone acetate, on the other hand, did not affect 3H-testosterone metabolism. Estradiol-17 β and cyproterone acetate inhibited in vitro binding of 3H-dihydrotestosterone to the intracellular cytoplasmic receptor, but not the intraluminal androgen binding protein (ABP). These data suggest that estradiol-17 β may have a more potent antiandrogenic effect on the epididymis than cyproterone acetate due to inhibition of 5 α reduction of testosterone as well as binding to the androgen receptor.
Comparative studies of androgen metabolism in theca and granulosa cells of human follicles in vitro
Moon,Duleba
, p. 419 - 430 (1982)
In eight separate experiments, theca and granulosa were isolated from human follicles (5-25 mm in diameter) , and their capacities to metabolize radiolabelled testosterone in 24 hour cultures were assessed. Theca metabolized testosterone primarily to androstenedione, however significant aromatization to estradiol-17β and to estrone was also observed. Granulosa metabolized testosterone primarily to estradiol-17β and estrone, while smaller quantities were converted to androstenedione. In seven of these experiments, the intermediate of aromatization, 19-hydroxytestosterone, was identified. In six of these experiments, theca, when compared to granulosa, produced more androstenedione but less estradiol-17β and estrone. 5α-Reduced androgens were non-detectable or produced in small quantities. In a single experiment, metabolism of androstenedione was compared to metabolism of testosterone by both theca and granulosa. Theca metabolized androstenedione to testosterone in smaller quantities than testosterone to androstenedione. Granulosa metabolized androstenedione to testosterone in higher quantities than testosterone to androstenedione. Both theca and granulosa aromatized androstenedione more readily than testosterone.
CONJUGATION OF ANDROGENS AND ESTROGENS BY HUMAN BREAST TUMORS IN VITRO
Raju, Uma,Blaustein, Ancel,Levitz, Mortimer
, p. 685 - 696 (1980)
The metabolism of 3H-androstenedione (Δ4-A) and 3H-estriol (E3) was studied in 12 human breast tumors.Part of each tumor was analyzed for estrogen receptor content.Aliquots of tumor homogenates were incubated for 2 hr separately with 3H-Δ4-A and 3H-E3 in the presence of appropriate cofactors.No distinct differences emerged in the profiles of the unconjugated metabolites of 3H-Δ4-A, the major compounds in the approximate order of descendence being androsterone, androstanedione, testosterone, 5α-androstane-3α,17β-diol, epiandrosterone, and dihydrotestosterone.One tumor homogenate from an infiltrating lobular carcinoma converted 3H-Δ4-A to glucosiduronate metabolites (11percent), of which androsterone, 6.4percent; testosterone, 1.6percent; and androstanediol, 0.6percent predominated.The homogenate of this tumor and two other tumors converted 3H-E3 to 3H-E3-3S.Conversions of E3 to E3-3S in the other tumor homogenates were less than 0.6percent.No correlation between receptor content and the capability of the tumor to conjugate Δ4-A or E3 evolved.However, correlations between steroid hormone metabolism and tumor histopathology may exist.
A molecularly imprinted receptor for separation of testosterone and epitestosterone, based on a steroidal cross-linker
Gavrilovi?, Ivana,Mitchell, Karen,Brailsford, Alan D.,Cowan, David A.,Kicman, Andrew T.,Ansell, Richard J.
, p. 478 - 483 (2011)
A series of molecularly imprinted polymers have been prepared and investigated as stationary phases in high performance liquid chromatography for the separation of testosterone and epitestosterone using non-polar mobile phases. The polymers were imprinted using 5α-dihydrotestosterone as template, and all retain testosterone more strongly than its 17α-OH epimer. The best polymer was prepared using trifluoromethylacrylic acid as functional monomer (interacting with the template via hydrogen bonds), divinylbenzene as 'inert' cross-linker, and chloroform as porogen. It also included a steroid-based cross-linker, which may interact with the template via van der Waals interactions to lend additional 'shape selectivity'. A 250 × 4.6 mm column packed with this polymer gave baseline resolution of testosterone and epitestosterone (15 μg each) in under 20 min. Preparation of the steroid based cross-linker included the selective reduction of 5α- dihydrotestosterone (17β-hydroxy-5α-androstan-3-one) to the 3α,17β-diol using K-selectride.
Glucosiduronidation and esterification of androsterone by human breast tumors in vitro
Raju,Kadner,Levitz,Kaganowicz,Blaustein
, p. 399 - 407 (1981)
The metabolism of 3H-androsterone was studied in homogenates (fortified with uridine 5'-diphosphoglucuronic acid and andenosine 3'- phosphate 5'-phosphosulfate) of eighteen breast tumors, one muscle underlying the primary breast carcinoma and metastatic axillary lymph nodes from a patient with suspected primary breast cancer. The major metabolites identified were less polar than androsterone. On saponification these lipoidal derivatives afforded androsterone as the only product (3 to 48%). Unmetabolized androsterone and lesser quantities of epiandrosterone, 5α-andorstane-3α, 17β-diol and 5α-androstane-3,17-dione comprised the free steroid fraction. Androsterone glucosiduronate was isolated (0.17-4.1%) from eight breast tumor homogenates and fromthe node tissue incubation (17%). There was no apparent correlation between glucuronyltransferase activity and histolpathology or estrogen receptor content.
Formation of 5α-dihydrotestosterone from 5α-androstane-3α,17β-diol in prostate cancer LAPC-4 cells – Identifying inhibitors of non-classical pathways producing the most potent androgen
Boutin, Sophie,Roy, Jenny,Maltais, René,Poirier, Donald
, (2020)
5α-Dihydrotestosterone (5α-DHT) possesses a great affinity for the androgen receptor (AR), and its binding to AR promotes the proliferation of prostate cancer (PC) cells in androgen-dependent PC. Primarily synthesized from testosterone (T) in testis, 5α-DHT could also be produced from 5α-androstane-3α,17β-diol (3α-diol), an almost inactive androgen, following non-classical pathways. We reported the chemical synthesis of non-commercially available [4-14C]-3α-diol from [4-14C]-T, and the development of a biological assay to identify inhibitors of the 5α-DHT formation from radiolabeled 3α-diol in LAPC-4 cell PC model. We measured the inhibitory potency of 5α-androstane derivatives against the formation of 5α-DHT, and inhibition curves were obtained for the most potent compounds (IC50 = 1.2–14.1 μM). The most potent inhibitor 25 (IC50 = 1.2 μM) possesses a 4-(4-CF3-3-CH3O-benzyl)piperazinyl methyl side chain at C3β and 17β-OH/17α-C[tbnd]CH functionalities at C17 of a 5α-androstane core.
STUDIES ON THE KINETICS OF THE INTERACTION OF 7α-HYDROXYTESTOSTERONE WITH THE STEROID 5α-REDUCTASE
Mittler, James C.
, p. 135 - 142 (1985)
Microsomal preparations from adult male rat testicular interstitial cells were incubated with tritiated testosterone.Added 7α-hydroxytestosterone, (7α,17β-dihydroxy-4-androsten-3-one), at levels which appear to exist in the adult testis, inhibited production of labelled 5α-reduced steroids in a graded fashion.This interaction is not competitive and occurs only at high substrate levels, such as those found in steroid-producing organs.Relationships to pubertal changes in steroid metabolism are discussed.
STUDY OF THE DIRECT EFFECT OF LHRH AGONIST ON TESTICULAR 17-HYDROXYLASE AND 5α-REDUCTASE ACTIVITIES IN NON-HYPOPHYSECTOMIZED ADULT RATS TREATED WITH AN ANTI-LUTEINIZING HORMONE SERUM
Carmichael, Rejean,Belanger, Alain
, p. 1 - 12 (1984)
In order to study both direct and pituitary-mediated mechanisms of action of the LHRH analogue 6, des-Gly-NH210>LHRH ethylamide upon testicular steroidogenesis in adult rat, we compared the effects of the agonist when administered alone or concomitantly with an anti-LH serum to non-hypophysectomized rats.Testicular steroid contents and in vitro progesterone and testosterone metabolism were determined.Anti-LH serum administration was able to prevent 5α-reductase stimulation by the agonistic peptide, but not the inhibition of 17-hydroxylase activity.These data suggest that modulation of 17-hydroxylase involves both direct and pituitary-mediated processes, while 5α-reductase stimulation is mainly if not only due to a pituitary-mediated mechanism.
Role of human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C3) in the extrahepatic metabolism of the steroidal aromatase inactivator Formestane
Wan, Runlan,Kong, Xi,Yang, Youzhe,Tao, Siwen,Chen, Youyou,Teichmann, Alexander Tobias,Wieland, Frank Heinrich
, (2019/12/23)
The clinical use of the steroidal aromatase inhibitor Formestane (4-hydroxandrostenedione, 4-OHA) in the treatment of advanced ER+ breast cancer has been discontinued, and therefore, interest in this remarkable drug has vanished. As a C-19 sterol, 4-OHA can undergo extensive intracellular metabolism depending on the expression of specific enzymes in the corresponding cells. We used the metabolites 4β-hydroxyandrosterone, 4β-hydroxyepiandrosterone and its 17β-reduced derivative as standards for the proof of catalytic activity present in the cell culture medium and expressed by the isolated enzymes. All of the aldo-keto reductases AKR1C1, AKR1C2, AKR1C3 and AKR1C4 catalysed the reduction of the 3-keto-group and the Δ4,5 double bond of 4-OHA at the same time. Molecular docking experiments using microscale thermophoresis and the examination of the kinetic behaviour of the isolated enzymes with the substrate 4-OHA proved that AKR1C3 had the highest affinity for the substrate, whereas AKR1C1 was the most efficient enzyme. Both enzymes (AKR1C1and AKR1C3) are highly expressed in adipose tissue and lungs, exhibiting 3β-HSD activity. The possibility that 4-OHA generates biologically active derivatives such as the androgen 4-hydroxytestosterone or some 17β-hydroxy derivatives of the 5α-reduced metabolites may reawaken interest in Formestane, provided that a suitable method of administration can be developed, avoiding oral or intramuscular depot-injection administration.
