- Steroidal isomers with uniform mass spectra of their per-TMS derivatives: Synthesis of 17-hydroxyandrostan-3-ones, androst-1-, and -4-ene-3,17-diols
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In human sports doping control analysis most of the steroids are analyzed after enzymatic hydrolysis of the glucuronides as per-trimethylsilyl (TMS) derivatives applying gas chromatography-mass spectrometry (GC-MS). According to the recommendations of the World Anti-Doping Agency the identification of analytes should be based on retention time and on mass spectrometric characterization. This study shows that the bis-TMS derivatives of 16 specific C19 steroids, namely the stereoisomers of 5ξ-androst-1-ene-3ξ,17ξ-diol (8 isomers), androst-4-ene-3ξ,17ξ-diol (4 isomers), and 17ξ-hydroxy-5ξ-androstan-3-one (4 isomers), reveal very similar mass spectra. As a rule, when taking the retention times, which are provided as Kovac indices for all these isomers, into account, a restriction to two or three possible isomers is possible. Reliable identification should additionally include a comparison of the retention times of the analytes with the reference compounds measured concomitantly. In some cases standard addition may be appropriate. Due to the limited availability, the above mentioned isomers were synthesized by reduction of the corresponding α,β-unsaturated oxo steroids either with K-Selectride or by catalytic hydrogenation (Pd/C as catalyst). The products of the reactions were identified by means of nuclear magnetic resonance (NMR) characterization and by further reduction to the corresponding 5ξ-androstane-3ξ,17ξ-diols and GC-MS comparison with commercially available reference standards.
- Parr, Maria K.,Zapp, Josef,Becker, Michael,Opfermann, Georg,Bartz, Ulrike,Schaenzer, Wilhelm
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- C-6α- vs C-7α-Substituted Steroidal Aromatase Inhibitors: Which Is Better? Synthesis, Biochemical Evaluation, Docking Studies, and Structure-Activity Relationships
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C-6α and C-7α androstanes were studied to disclose which position among them is more convenient to functionalize to reach superior aromatase inhibition. In the first series, the study of C-6 versus C-7 methyl derivatives led to the very active compound 9 with IC50 of 0.06 μM and Ki = 0.025 μM (competitive inhibition). In the second series, the study of C-6 versus C-7 allyl derivatives led to the best aromatase inhibitor 13 of this work with IC50 of 0.055 μM and Ki = 0.0225 μM (irreversible inhibition). Beyond these findings, it was concluded that position C-6α is better to functionalize than C-7α, except when there is a C-4 substituent simultaneously. In addition, the methyl group was the best substituent, followed by the allyl group and next by the hydroxyl group. To rationalize the structure-activity relationship of the best inhibitor 13, molecular modeling studies were carried out.
- Roleira, Fernanda M. F.,Varela, Carla,Amaral, Cristina,Costa, Saul C.,Correia-Da-Silva, Georgina,Moraca, Federica,Costa, Giosuè,Alcaro, Stefano,Teixeira, Natércia A. A.,Tavares Da Silva, Elisiário J.
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- Concerning the pathway from 19-oxoandrost-4-ene-3,17-dione
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The conversion of a molecule of 19-oxoandrost-4-ene-3,17-dione to estrone by human placental aromatase requires a molecule of oxygen and NADPH.An atom of this molecule of oxygen is incorporated into the extruded formic acid derived from C-19 af .It was proposed that the O2 is utilized for the enzymatic 2β-hydroxylation of and the released intermediate 2β-hydroxy-19-oxoandrost-4-ene-3,17-dione aromatizes nonenzymatically.Should be an obligatory intermediate of estrogen biosynthesis, then all the oxygen of its 2β-hydroxyl must be incorporated into the extruded formic acid.We have previously synthesized 18O;19-3H> and proved that none of its 2β-18O was incorporated in the formic acid extruded in the aromatization.On this basis we concluded that can not be an obligatory precursor of estrogen biosynthesis.The trapping of radioactive androst-4-ene-2β,3β,17β,19-tetrol in a reductively terminated incubation of a mixture of radioactive androst-4-ene-3,17-dione and with crude placental aromatase was interpreted as evidence in support of the intermediacy of .We confirmed that the terol can indeed be trapped in the reductively terminated incubations.However, considering that the crude placental enzyme preparation very likely contains numerous activated oxygen species capable of a variety of oxidation reactions, most of which may not be related to estrogen elaboration, and in view of our results qoted above, the origin and the eventual biosynthetic role of the parent compound of the tetrol remains to be determined.
- Caspi, Eliahu,Njar, Vincent C. O.
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- Identification by gas chromatography mass spectrometry of intermediates in the aromatization of modified C19 steroids by human placental microsomes
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Analogs of 4 androstene 3,17 dione and testosterone were tested as substrates for the aromatizing enzyme complex of human placenta. Compounds modified in rings B, C, and D were found to be aromatized via a pathway similar to that postulated for 4 androstene 3,17 dione and testosterone, in which oxidation to the 19 hydroxy and 19 oxo (or corresponding gem diol) intermediates occurs. No evidence of additional intermediates was obtained.
- Braselton Jr,Orr,Engel
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- The Reduction of Steroid 2α-Fluoro 4-En-3-ones
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Reduction of testosterone with potassium tri-(R,S)-sec-butylborohydride gives predominantly the allylic 3β-alcohol, while 2α-fluorotestosterone is converted solely to 2α-fluoro-4-androstene-3α,17β-diol, and 2α-fluoro-4-androstene-3,17-dione to 2α-fluoro-3α-hydroxy-4-androsten-17-one.Reduction of testosterone with (R,R)- or (S,S)-Rh-DIOP and dihydrosilanes give predominantly allylic alcohols, while with the same catalysts and monohydrosilanes no allylic alcohols are found, the 4-double bond being instead reduced.The chirality of the DIOP reagents contributes only to a minor extent to stereoselectivity of 3-ketone reduction.
- Goeendos, Gyoergy,McGirr, Larry G.,Jablonski, Chester R.,Snedden, Walter,Orr, James C.
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- Boosting the Catalytic Performance of Metal–Organic Frameworks for Steroid Transformations by Confinement within a Mesoporous Scaffold
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Solid-state crystallization achieves selective confinement of metal–organic framework (MOF) nanocrystals within mesoporous materials, thereby rendering active sites more accessible compared to the bulk-MOF and enhancing the chemical and mechanical stability of MOF nanocrystals. (Zr)UiO-66(NH2)/SiO2 hybrid materials were tested as efficient and reusable heterogeneous catalysts for the synthesis of steroid derivatives, outperforming the bulk (Zr)UiO-66(NH2) MOF. A clear correlation between the catalytic activity of the dispersed Zr sites present in the confined MOF, and the loading of the mesoporous SiO2, is demonstrated for steroid transformations.
- Cirujano, Francisco G.,Luz, Ignacio,Soukri, Mustapha,Van Goethem, Cedric,Vankelecom, Ivo F. J.,Lail, Marty,De Vos, Dirk E.
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- Chemoselective Luche-Type Reduction of α,β-Unsaturated Ketones by Magnesium Catalysis
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The chemoselective reduction of α,β-unsaturated ketones by use of an economic and readily available Mg catalyst has been developed. Excellent yields for a wide range of ketones have been achieved under mild reaction conditions, short times, and low catalyst loadings (0.2-0.5 mol %).
- Jang, Yoon Kyung,Magre, Marc,Rueping, Magnus
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supporting information
p. 8349 - 8352
(2019/10/16)
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- Synthesis of steroid bisglucuronide and sulfate glucuronide reference materials: Unearthing neglected treasures of steroid metabolism
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Doubly or bisconjugated steroid metabolites have long been known as minor components of the steroid profile that have traditionally been studied by laborious and indirect fractionation, hydrolysis and gas chromatography-mass spectrometry (GC–MS) analysis. Recently, the synthesis and characterisation of steroid bis(sulfate) (aka disulfate or bis-sulfate) reference materials enabled the liquid chromatography-tandem mass spectrometry (LC–MS/MS) study of this metabolite class and the development of a constant ion loss (CIL) scan method for the direct and untargeted detection of steroid bis(sulfate) metabolites. Methods for the direct LC–MS/MS detection of other bisconjugated steroids, such as steroid bisglucuronide and mixed steroid sulfate glucuronide metabolites, have great potential to reveal a more complete picture of the steroid profile. However, access to steroid bisglucuronide or sulfate glucuronide reference materials necessary for LC–MS/MS method development, metabolite identification or quantification is severely limited. In this work, ten steroid bisglucuronide and ten steroid sulfate glucuronide reference materials were synthesised through an ordered combination of chemical sulfation and/or enzymatic glucuronylation reactions. All compounds were purified and characterised using NMR and MS methods. Chemistry for the preparation of stable isotope labelled steroid {13C6}-glucuronide internal standards has also been developed and applied to the preparation of two selectively mono-labelled steroid bisglucuronide reference materials used to characterise more completely MS fragmentation pathways. The electrospray ionisation and fragmentation of the bisconjugated steroid reference materials has been studied. Preliminary targeted ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis of the reference materials prepared revealed the presence of three steroid sulfate glucuronides as endogenous human urinary metabolites.
- Pranata, Andy,Fitzgerald, Christopher C.,Khymenets, Olha,Westley, Erin,Anderson, Natasha J.,Ma, Paul,Pozo, Oscar J.,McLeod, Malcolm D.
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supporting information
p. 25 - 40
(2019/01/04)
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- An easy stereoselective synthesis of 5(10)-estrene-3β,17α-diol, a biological marker of pregnancy in the mare
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5(10)-Estrene-3β,17α-diol is an essential reference material for doping analysis in horse-racing laboratories. It is used to detect misuse, for doping purpose, of the pregnancy status in the mare. Its stereoselective synthesis from 17β-estradiol-3-methyl ether (prepared from estrone or 17β-estradiol) was performed in four steps: (1) Mitsunobu inversion of the 17β-alcohol; (2) Birch reduction of the aromatic ring; (3) stereoselective reduction of the 3-ketone via Noyori asymmetric transfer hydrogenation; (4) chemoenzymatic purification.
- Balssa, Frédéric,Fischer, Michael,Bonnaire, Yves
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- New structure-activity relationships of A-and D-ring modified steroidal aromatase inhibitors: Design, synthesis, and biochemical evaluation
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A- and D-ring androstenedione derivatives were synthesized and tested for their abilities to inhibit aromatase. In one series, C-3 hydroxyl derivatives were studied leading to a very active compound, when the C-3 hydroxyl group assumes 3β stereochemistry (1, IC50 = 0.18 μM). In a second series, the influence of double bonds or epoxide functions in different positions along the A-ring was studied. Among epoxides, the 3,4-epoxide 15 showed the best activity (IC50 = 0.145 μM) revealing the possibility of the 3,4-oxiran oxygen resembling the C-3 carbonyl group of androstenedione. Among olefins, the 4,5-olefin 12 (IC50 = 0.135 μM) revealed the best activity, pointing out the importance of planarity in the A,B-ring junction near C-5. C-4 acetoxy and acetylsalicyloxy derivatives were also studied showing that bulky substituents in C-4 diminish the activity. In addition, IFD simulations helped to explain the recognition of the C-3 hydroxyl derivatives (1 and 2) as well as 15 within the enzyme.
- Varela, Carla,Tavares Da Silva, Elisiário J.,Amaral, Cristina,Correia Da Silva, Georgina,Baptista, Teresa,Alcaro, Stefano,Costa, Giosuè,Carvalho, Rui A.,Teixeira, Natércia A. A.,Roleira, Fernanda M. F.
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experimental part
p. 3992 - 4002
(2012/07/30)
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- Reduction of steroidal ketones with amine - Boranes
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Complexes of secondary amines with borane, R2NH·BH 3, surpass sodium borohydride as reducing agents for saturated and unsaturated steroidal 3-, 12-, 17-, and 20-ketones as regards chemo- and regioselectivity and mildness of the reaction conditions. In the case of 12-ketones, stereoselectivity is also improved.
- Leontjev,Vasiljeva,Pivnitsky
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p. 703 - 708
(2007/10/03)
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- Methods and compositions for attracting and controlling termites
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The present invention provides a composition for attracting termites containing a steroid derivative of formula I The present invention also provides a method for attracting or controlling termites with the composition.
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- Steroid transformations with Exophiala jeanselmei var. lecanii-corni and Ceratocystis paradoxa
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The fungi Exophiala jeanselmei var. lecanii-corni [IMI (International Mycological Institute) 312989, UAMH (University of Alberta Microfungus Collection and Herbarium) 8783] and Ceratocystis paradoxa (IMI 374529, UAMH 8784) have been examined for their potential in steroid biotransformation. The study has determined that E. jeanselmei var. lecanii-corni effected overall anti-Markovnikov hydration on dehydroisoandrosterone, and side-chain degradation on a variety of pregnanes. Both ascomycetes were found to carry out redox reactions of alcohols and ketones as well as 1,4 reduction of α,β-unsaturated carbonyl systems.
- Porter, Roy B.R.,Gallimore, Winklet A.,Reese, Paul B.
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p. 770 - 779
(2007/10/03)
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- Methods and compositions for attracting and controlling termites
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The present invention provides a composition for attracting termites containing a steroid derivative of formula I The present invention also provides a method for attracting or controlling termites with the composition.
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- Chemoselective reductions with sodium borohydride
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Under the appropriate reaction conditions, sodium borohydride is a highly chemoselective reducing agent.The order of reactivity among carbonyl groups is conjugated enonesketonesconjugated aldehydesaldehydes.In general, a carbonyl group of one type can be selectively reduced in the presence of a carbonyl group of a less reactive type.Reactions are conducted with excess sodium borohydride at -78 deg C in solvent mixtures of methanol or ethanol in dichloromethane.Key words: sodium borohydride, chemoselective reductions.
- Ward, Dale E.,Rhee, Chung K.
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p. 1206 - 1211
(2007/10/02)
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- A GENERAL METHOD FOR THE SELECTIVE REDUCTION OF KETONES IN THE PRESENCE OF ENONES.
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Ketones can be reduced in the presence of conjugated enones by sodium borohydride in 50percent methanol in dichloromethane at -78 deg C.The selectivity is generally excellent.In favorable cases the reaction can be carried out at room temperature in dichloromethane with acetic acid as catalyst.
- Ward, Dale E.,Rhee, Chung K.,Zoghaib, Wajdi M.
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p. 517 - 520
(2007/10/02)
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- SELECTIVITE DE LA REDUCTION D'α-ENONES POLYCYCLIQUES PAR LES BOROHYDRURES: EFFET DE L'ADDITION DE TETRAMETHYL-ETHYLENEDIAMINE AU BOROHYDRURE DE TETRABUTYLAMMONIUM
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Δ1,9octalone, Δ1,9-10-methyl octalone and testosterone were reduced by NBu4BH4, alone or in the presence of tetramethylethylenediamine (TMEDA), in THF and in toluene.With TMEDA, the first step of the reduction is the regioselective 1,4 attack by BH4(1-) which leads either to the saturated ketones or to the corresponding saturated alcohols.The results observed under different conditions were interpreted by the intervention of various reductive species: diborane, enoxyborohydrides in the absence of TMEDA, amine-borane in its presence.
- D'incan, E.,Loupy, A.,Maia, A.,Seyden-Penne, J.,Viout, P.
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p. 2923 - 2927
(2007/10/02)
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- Lanthanoids in Organic Synthesis. 6. The Reduction of α-Enones by Sodium Borohydride in the Presence of Lanthanoid Chlorides: Synthetic and Mechanistic Aspects
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Lanthanoid chlorides (LnCl3) are efficient catalysts for the regioselective 1,2-reduction of α-enones by NaBH4 in methanol solution.Optimal conditions of this reaction have been determined.A mechanistic interpretation depicting the role of the Ln3+ ions is given.The major effect of Ln3+ is the catalysis of BH4- decomposition by the hydroxylic solvent to afford alkoxyborohydrides, which may be responsible for the observed regioselectivity.The stereoselectivity of the process is also modified by the presence of the Ln3+ ions, in that axial attack of cyclohexanone systems is enhanced.
- Gemal, Andre L.,Luche, Jean-Louis
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p. 5454 - 5459
(2007/10/02)
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- NITROGENOUS ANALOGS OF STEROIDS. PART XI. SYNTHESIS OF B-HOMO-5-AZAANDROSTA-3β,17β-DIOL BY MULTISTAGE TESTOSTERONE TRANSFORMATION
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The synthesis of B-homo-5-azaandrosta-3β,17β-diol (9a) from testosterone (1b), through 3β,17β-diacetoxyandrost-4-ene (2b), secoaldehyde 3, triester 4c, its oxime 6, 3β,17β-dihydroxy-4,5-seco-B-homo-5-azaandrostan-4-oic acid (7a), 3β,17β-diacetoxy-B-homo-5-azaandrosta-4,5a-dione (8) and reduction of 8 with LAH, is described.
- Rodewald, Wladyslaw J.,Zaworska, Alicja
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p. 1147 - 1154
(2007/10/02)
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