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Steroids Apr 1981The metabolism of 3H-androsterone was studied in homogenates (fortified with uridine 5'-diphosphoglucuronic acid and adenosine 3'-phosphate 5'-phosphosulfate) of...
The metabolism of 3H-androsterone was studied in homogenates (fortified with uridine 5'-diphosphoglucuronic acid and adenosine 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, 5 alpha-androstane- alpha, 17 beta-diol and 5 alpha-androstane-3,17-dione comprised the free steroid fraction. Androsterone glucosiduronate was isolated (0.17-4.1%) from weight breast tumor homogenates and from the node tissue incubation (17%). There was no apparent correlation between glucuronyltransferase activity and histopathology or estrogen receptor content.
Topics: Adenofibroma; Androsterone; Breast Neoplasms; Carcinoma; Esterification; Female; Humans; In Vitro Techniques
PubMed: 7245287
DOI: 10.1016/0039-128x(81)90042-8 -
The Journal of Biological Chemistry Jan 2004In steroid biosynthesis, human dehydroepiandrosterone sulfotransferase (DHEA-ST) in the adrenals has been reported to catalyze the transfer of the sulfonate group from...
Identifying androsterone (ADT) as a cognate substrate for human dehydroepiandrosterone sulfotransferase (DHEA-ST) important for steroid homeostasis: structure of the enzyme-ADT complex.
In steroid biosynthesis, human dehydroepiandrosterone sulfotransferase (DHEA-ST) in the adrenals has been reported to catalyze the transfer of the sulfonate group from 3'-phosphoadenosine-5'-phosphosulfate to dehydroepiandrosterone (DHEA). DHEA and its sulfate play roles as steroid precursors; however, the role of the enzyme in the catabolism of androgens is poorly understood. Androsterone sulfate is clinically recognized as one of the major androgen metabolites found in urine. Here it is demonstrated that this enzyme recognizes androsterone (ADT) as a cognate substrate with similar kinetics but a 2-fold specificity and stronger substrate inhibition than DHEA. The structure of human DHEA-ST in complex with ADT has been solved at 2.7 A resolution, confirming ADT recognition. Structural analysis has revealed the binding mode of ADT differs from that of DHEA, despite the similarity of the overall structure between the ADT and the DHEA binary complexes. Our results identify that this human enzyme is an ADT sulfotransferase as well as a DHEA sulfotransferase, implying an important role in steroid homeostasis for the adrenals and liver.
Topics: Adrenal Glands; Androsterone; Binding Sites; Homeostasis; Humans; Kinetics; Liver; Protein Conformation; Structure-Activity Relationship; Substrate Specificity; Sulfotransferases
PubMed: 14573603
DOI: 10.1074/jbc.M310446200 -
Journal of Medicinal Chemistry Aug 2019Decreasing the intratumoral androgen biosynthesis by using an inhibitor of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a strategy to treat prostate cancer....
A- and D-Ring Structural Modifications of an Androsterone Derivative Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3: Chemical Synthesis and Structure-Activity Relationships.
Decreasing the intratumoral androgen biosynthesis by using an inhibitor of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is a strategy to treat prostate cancer. The androsterone (ADT) derivative (RM-532-105) has shown strong inhibitory activity on 17β-HSD3, but needs to be improved. Herein, we describe the chemical synthesis and characterization of two series of analogues to address the impact of A- and D-ring modifications on 17β-HSD3 inhibitory activity, androgenic effect, and metabolic stability. Structure-activity relationships were generated by adding different groups at C16/C17 (D-ring diversification) or replacing the ADT backbone by a nor-androstane or an estrane backbone (A-ring diversification). D-ring derivatives were less potent inhibitors than lead compound , whereas steroidal backbone (A-ring) change led to identifying promising novel estrane derivatives. This culminated with potent 17β-HSD3 inhibitors , , , and (IC = 0.10, 0.02, 0.13, and 0.17 μM, respectively), which did not stimulate LAPC-4 cell proliferation and displayed higher plasma concentration in mice than lead compound .
Topics: 17-Hydroxysteroid Dehydrogenases; Androsterone; Animals; Cell Line, Tumor; Enzyme Inhibitors; Female; Humans; Male; Mice; Prostatic Neoplasms; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship
PubMed: 31268309
DOI: 10.1021/acs.jmedchem.9b00624 -
Tidsskrift For Den Norske Laegeforening... Mar 1967
Topics: Androsterone; Anticholesteremic Agents; Butyrates
PubMed: 6039533
DOI: No ID Found -
Steroids Feb 1975The 7-carboxymethoximino derivative of androsterone (1) has been prepared from dehydroisoandrosterone-17-ethyleneketal by a sequence involving inversion at C-3,...
The 7-carboxymethoximino derivative of androsterone (1) has been prepared from dehydroisoandrosterone-17-ethyleneketal by a sequence involving inversion at C-3, introduction of a carbonyl at C-7, and reduction of the double bond at C-5. The substance was condensed with BSA by the carbodiimide procedure to afford a conjugate which produced anti-androsterone antiserum in innoculated rabbits. The antiserum is sufficiently active to be useful in radioimmunoassay procedures.
Topics: Androsterone; Animals; Antigens; Biological Assay; Cattle; Chromatography, Gas; Dehydroepiandrosterone; Dose-Response Relationship, Drug; Methods; Rabbits; Radioimmunoassay; Serum Albumin, Bovine
PubMed: 123368
DOI: 10.1016/s0039-128x(75)90016-1 -
Steroids Apr 2013The 1,3-dipolar cycloaddition of azomethine ylide derived in situ from the reaction of acenaphthylene-1,2-dione and 1,3-thiazolane-4-carboxylic acid to various exocyclic...
The 1,3-dipolar cycloaddition of azomethine ylide derived in situ from the reaction of acenaphthylene-1,2-dione and 1,3-thiazolane-4-carboxylic acid to various exocyclic dipolarophiles synthesized from trans-androsterone and trans-dehydroandrosterone afforded a library of novel spiro[5'.2″]acenaphthylene-1″-one-spiro[16.6']-(7'-aryl)-tetrahydro-1H-pyrrolo [1,2-c][1,3]thiazolo-trans-androsterone/dehydroandrosterone hybrid heterocycles respectively. These reactions proceeded stereo-specifically affording a single isomer of the 16-spiro steroids in excellent yields.
Topics: Acenaphthenes; Androsterone; Heterocyclic Compounds; Models, Molecular; Molecular Conformation; Spiro Compounds
PubMed: 23376110
DOI: 10.1016/j.steroids.2012.12.017 -
Bioorganic & Medicinal Chemistry Letters Dec 2013Spiromorpholinone derivatives were synthesized from androsterone or cyclohexanone in 6 or 3 steps, respectively, and these scaffolds were used for the introduction of a...
Spiromorpholinone derivatives were synthesized from androsterone or cyclohexanone in 6 or 3 steps, respectively, and these scaffolds were used for the introduction of a hydrophobic group via a nucleophilic substitution. Non-steroidal spiromorpholinones are not active as inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3), but steroidal morpholinones are very potent inhibitors. In fact, those with (S) stereochemistry are more active than their (R) homologues, whereas N-benzylated compounds are more active than their non substituted precursors. The target compounds exhibited strong inhibition of 17β-HSD3 in rat testis homogenate (87-92% inhibition at 1 μM).
Topics: 17-Hydroxysteroid Dehydrogenases; Androsterone; Animals; Enzyme Inhibitors; Male; Rats; Structure-Activity Relationship; Testis
PubMed: 24144853
DOI: 10.1016/j.bmcl.2013.09.072 -
Journal of Medicinal Chemistry Feb 2012The enantiomer pair androsterone and ent-androsterone are positive allosteric modulators of γ-aminobutyric acid (GABA) type A receptors. Each enantiomer was shown to...
The enantiomer pair androsterone and ent-androsterone are positive allosteric modulators of γ-aminobutyric acid (GABA) type A receptors. Each enantiomer was shown to bind at the same receptor site. Binding orientations of the enantiomers at this site were deduced using enantiomer pairs containing OBn substituents at either C-7 or C-11. 11β-OBn-substituted steroids and 7α-OBn-substituted ent-steroids potently displace [(35)S]-tert-butylbicyclophosphorothionate, augment GABA currents, and anesthetize tadpoles. In contrast, 7β-OBn-substituted steroids and 11α-OBn-substituted ent-steroids have diminished actions. The results suggest that the binding orientations of the active analogues are inverted relative to each other with the 7α- and 11β-substituents similarly located on the edges of the molecules not in contact with the receptor surface. Analogue potentiation of the GABA current was abrogated by an α(1) subunit Q241L mutation, indicating that the active analogues act at the same sites in α(1)β(2)γ(2L) receptors previously associated with positive neurosteroid modulation.
Topics: Allosteric Site; Androsterone; Animals; Binding, Competitive; Brain; Female; In Vitro Techniques; Larva; Models, Molecular; Neurotransmitter Agents; Oocytes; Patch-Clamp Techniques; Protein Binding; Radioligand Assay; Rats; Receptors, GABA-A; Reflex; Stereoisomerism; Structure-Activity Relationship; Xenopus laevis
PubMed: 22191644
DOI: 10.1021/jm2014925 -
Journal of Medicinal Chemistry Aug 2005Type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is involved in the biosynthesis of androgen testosterone. To produce potent inhibitors of this key steroidogenic...
Androsterone 3alpha-ether-3beta-substituted and androsterone 3beta-substituted derivatives as inhibitors of type 3 17beta-hydroxysteroid dehydrogenase: chemical synthesis and structure-activity relationship.
Type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD) is involved in the biosynthesis of androgen testosterone. To produce potent inhibitors of this key steroidogenic enzyme, we prepared a series of androsterone (ADT) derivatives by adding a variety of substituents at position 3. The 3beta-substituted ADT derivatives proved to be good inhibitors (IC(50) = 57-147 nM) with better inhibitory activities obtained for compounds bearing a propyl, s-butyl, cyclohexylalkyl, or phenylalkyl group. With an IC(50) value of 57 nM, the 3beta-phenylmethyl-ADT was 6-fold more potent than ADT, the lead compound, and 13-fold more potent than 4-androstene-3,17-dione, the natural enzyme substrate used itself as inhibitor. The 3alpha-ether-3beta-substituted ADT derivatives had a lower inhibitory activity compared to the 3beta-substituted ADT analogues except for the 3beta-phenylethyl-3alpha-methl-O-ADT (IC(50) = 73 nM), which proved to be a more potent inhibitor than 3beta-phenylethyl-ADT (IC(50) = 99 nM). The results of our study identified potent type 3 17beta-HSD inhibitors for potential use in the treatment of androgen-sensitive diseases.
Topics: 17-Hydroxysteroid Dehydrogenases; Androsterone; Cell Line; Ethers; Humans; Structure-Activity Relationship
PubMed: 16078844
DOI: 10.1021/jm058179h -
Psychopharmacology Sep 2014Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5β-epimer etiocholanolone [(3α,5β)-3-hydroxyandrostan-17-one; 5β,3α-A)], the major excreted...
RATIONALE
Androsterone [(3α,5α)-3-hydroxyandrostan-17-one; 5α,3α-A] and its 5β-epimer etiocholanolone [(3α,5β)-3-hydroxyandrostan-17-one; 5β,3α-A)], the major excreted metabolites of testosterone, are neurosteroid positive modulators of GABAA receptors. Such neurosteroids typically show enantioselectivity in which the natural form is more potent than the corresponding unnatural enantiomer. For 5α,3α-A and 5β,3α-A, the unnatural enantiomers are more potent at GABAA receptors than the natural forms.
OBJECTIVES
The aim of this study was to compare the anticonvulsant potencies and time courses of 5α,3α-A and 5β,3α-A with their enantiomers in mouse seizure models.
METHODS
Steroids were administered intraperitoneally to male NIH Swiss mice 15 min (or up to 6 h in time course experiments) prior to administration of an electrical stimulus in the 6-Hz or maximal electroshock (MES) seizure tests or the convulsant pentylenetetrazol (PTZ).
RESULTS
In the 6-Hz test, the ED50 values of ent-5α,3α-A was 5.0 mg/kg whereas the value for 5α,3α-A was 12.1 mg/kg; the corresponding values in the PTZ seizure test were 22.8 and 51.8 mg/kg. Neurosteroid GABAA receptor-positive allosteric modulators are generally weak in the MES seizure test and this was confirmed in the present study. However, the atypical relative potency relationship was maintained with ED50 values of 140 and 223 mg/kg for ent-5α,3α-A and 5α,3α-A, respectively. Similar relationships were obtained for the 5β-isomers, except that the enantioselectivity was accentuated. In the 6-Hz and PTZ tests, the ED50 values of ent-5β,3α-A were 11.8 and 20.4 mg/kg whereas the values for 5β,3α-A were 57.6 and 109.1 mg/kg. Protective activity in the 6-Hz test of ent-5α,3α-A persisted for somewhat longer (~5 h) than for 5α,3α-A (~4 h); protection by ent-5β,3α-A also persisted longer (~3 h) than for 5β,3α-A (~2 h).
CONCLUSIONS
The unnatural enantiomers of 17-keto androgen class neurosteroids have greater in vivo potency and a longer duration of action than their natural counterparts. The more prolonged duration of action of the unnatural enantiomers could reflect reduced susceptibility to metabolism. Unnatural enantiomers of androgen class neurosteroids could have therapeutic utility and may provide advantages over the corresponding natural isomers due to enhanced potency and improved pharmacokinetic characteristics.
Topics: Androsterone; Animals; Anticonvulsants; Behavior, Animal; Convulsants; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Electroshock; Etiocholanolone; Male; Mice; Neurotransmitter Agents; Pentylenetetrazole; Stereoisomerism; Structure-Activity Relationship
PubMed: 24705905
DOI: 10.1007/s00213-014-3546-x