Synthesis of 17α-bromovinyl- and 17α-iodovinylnortestosterone derivatives

Depending upon the reaction conditions, norethisterone (1) and its ketal 2 can be transformed with tributyltin hydride to either the (E)-or(Z)-17α-(2-tributylstannylvinyl)-nortestosterone derivatives 3, 8 and 13. Further treatment with N-bromo- or N-iodosuccinimide yields the corresponding (E)- and (Z)-17α-halovinyl steroids 6,7,10 and 11. Radio-labelled (Z)-17α-(2-iodovinyl)-nortestosterone was prepared by reaction of the 17α-stannylvinyl derivative 13 with Na¹²⁵I.     

13C NMR spectra of 17-substituted epimeric 17α and 17β-ethynylandrostenes and their hexacarbonyldicobalt complexes

¹³C NMR spectra of epimeric 17-R-substituted 17-ethynylandrostenes (R = H, OH, OAc, OMe, NCS) and 17-R-substituted 17-ethynylandrostenes (R = H, OH, OAc, OMe), and their hexacarbonyldicobalt complexes, as well as of ¹⁶-17-ethynylandrostenes and their hexacarbonyldicobalt complexes have been studied. Stereochemical dependence of C(12), C(14), C(18), C(20) and C(21) chemical shifts on the configuration of the substituents at C(17) has been demonstrated. The effect of Co-complexation on the spectral characteristics of Co-coordinated 17-ethynylandrostenes in both Stereochemical series has been investigated.Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 1, pp. 212–216, January, 1993.     

The yin and yang of amyloid: insights from α-synuclein and repeat domain of Pmel17

Amyloid has been traditionally viewed in the context of disease. However, the emerging concept of 'functional amyloid' has taken a new direction into how we view amyloid. Recent studies have identified amyloid fibrils ranging from bacteria to humans that have a beneficial role, instead of being associated with a misfolded state that has been implicated in diseases such as Alzheimer's, Parkinson's and prion diseases. Here, we review our work on two human amyloidogenic polypeptides, one associated with Parkinson's disease, α-synuclein (α-syn), and the other important for melanin synthesis, the repeat domain (RPT) from Pmel17. Particularly, we focused our attention on spectroscopic studies of protein conformation and dynamics and their impact on α-syn amyloid formation and for RPT, we discussed the strict pH dependence of amyloid formation and its role in melanin biosynthesis.     

Synthesis of nitrogen-containing derivatives of 17(20)-pregnenoic, 17β-hydroxypregnanoic,and 17α-hydroxypregnanoic acids as new potential antiandrogens

A general scheme for the synthesis of oxazoline and benzoxazole derivatives of [17(20)E]-21-norpregnene differing in the structure of the steroid moiety as well as amides of 17β-hydroxy-3-oxopregn-4-en-21-oic and 17α-hydroxy-3-oxopregn-4-en-21-oic acids was developed. The scheme involved synthesis of the steroid building blocks (appropriately protected derivatives of pregn-17(20)-en-21-oic, 17β-hydroxypregnan-21-oic, and 17α-hydroxypregnan-21-oic acids) and subsequent transformation of these building blocks into the target compounds. Following the developed scheme, synthesis of new nitrogen-containing steroid derivatives exhibiting antiandrogenic activity was enabled.     

Characterization of 17α-hydroxysteroid dehydrogenase activity (17α-HSD) and its involvement in the biosynthesis of epitestosterone

Background  

Epi-testosterone (epiT) is the 17α-epimer of testosterone. It has been found at similar level as testosterone in human biological fluids. This steroid has thus been used as a natural internal standard for assessing testosterone abuse in sports. EpiT has been also shown to accumulate in mammary cyst fluid and in human prostate. It was found to possess antiandrogenic activity as well as neuroprotective effects. So far, the exact pathway leading to the formation of epiT has not been elucidated.     

Electron-transfer induced cleavage and formation of C-H-bonds in 17ē and 19ē platinum complexes

The electrochemical behavior of platinum complexes [Pt(⁴-diene)(⁵-C₅R₅)]⁺BF₄ ^– (1 ⁺, diene = C₅Me₅H, R = H;2 ⁺, diene = C₅Me₅H, R = Me;3 ⁺, diene = C₆H₈, R = Me;4 ⁺, diene = C₈H₁₂, R = Me) was studied by cyclic voltammetry. Complexes1 ⁺ and2 ⁺ are shown to be capable of both oxidation and reduction. One-electron reduction of2 ⁺ gives a mixture of two neutral isomeric complexes5a,b of ³-allylic and ,,-olefinic type due to the cleavage of C-H bonds in the methyl groups of the pentamethylcyclopentadiene ligand of 19 complexes2. The preparative electrochemical oxidation of2 ⁺ results in cleavage of the C-H bond at the sp³-hybridized pentamethylcyclopentadiene carbon atom in 17 dication radical2 ²⁺ to give the decamethylplatinocene dication [Pt(⁵-C₅Me₅)₂]²⁺(BF₄)₂ (7 ²⁺). It is shown that one-electron reduction of7 ²⁺ and one-electron oxidation of5a,b is accompanied by the formation of C-H bonds to form2 ⁺.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1153–1157, June, 1995.This work was carried out with financial support from the Russian Foundation for Basic Research (Project No. 94-03-08598).     

Reactivity of Hydroxy and Keto Groups on C-6 and C-17 of 3α,5α-Cycloandrostanes

Convenient methods for preparing several 3,5-cycloandrostanes have been developed in order to synthesize the phytoecdysteroid rubrosterone. Certain of their chemical transformations were studied     

Effects of 17α-ethinylestradiol on zoo- and phytoplankton in lentic microcosms

The effects of 17-ethinylestradiol (EE), an endocrine disruptor, on zoo- and phytoplankton were studied in outdoor 230-L still-water microcosms. Cell density and biomass, diversity, and community composition were analyzed. Five microcosms were treated by controlled release for six weeks, three by direct application of EE. To investigate recovery, sampling was continued for four weeks after treatment. Most characteristics of the zooplankton were not unambiguously affected by EE. Only the relative density of copepods, especially of their larvae, decreased significantly after EE application. For phytoplankton, no unambiguous concentration- or toxodose-correlated effects on any biotic characteristics could be found. However, most properties of the phytoplankton deviated from those of controls, i.e. tended to be smaller (number of species per microcosm, biomass, cell density) or covered a wider range (diversity, evenness). PCA indicated a shift of species structure in the treated microcosms. This was supported by the species scores calculated by the principal response curve method, although the principal response curve itself showed no clear EE-correlated shifts. High variability within the biocenosis between microcosms and over time, probably because of disturbance of the ecosystem before starting of the test, might have superimposed EE-dependent effects.Abbreviations c _dt Canonical coefficient - CRD Controlled-release device - E Shannon–Wiener index for evenness - EC10 Effect concentration for 10% of maximum effect - EC50 Effect concentration for 50% of maximum effect - EE 17-Ethinylestradiol - H Shannon–Wiener index for diversity - LPDE Low density polyethylene - NOEC No observed effect concentration - PCA Principal component analysis - PRC Principal response curve - RDA Redundancy analysis - SD Standard deviation     

Ionic liquid-promoted Wagner-Meerwein rearrangement of 16α,17α-epoxyandrostanes and 16α,17α-epoxyestranes

Ionic liquids 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim](+)[PF(6)](-)) and 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim](+)[BF(4)](-)) were found to promote an unusual Wagner-Meerwein rearrangement of steroidal 16α,17α-epoxides leading to unnatural 13-epi-18-nor-16-one derivatives as the main products. These compounds were isolated in good to excellent yields. 16α-Hydroxy-Δ(13)-18-norsteroids, the results of the usual rearrangement, were obtained as minor components of the reaction mixtures. The ionic liquid [bmim](+)[PF(6)](-) was shown to induce C-ring aromatization of 16α,17α-epoxyestranes due to the formation of HF, the hydrolysis product of [PF(6)](-). Increasing amounts of HF and [PO(2)F(2)](-) were detected by (19)F and (31)P NMR when the ionic liquid was reused. The structures of the steroidal products, 16-oxo-18-nor-13α-steroid derivatives, 16α-hydroxy-Δ(13)-18-norsteroids, and C-aromatic compounds were determined by two-dimensional NMR techniques and high-resolution mass spectrometry (HRMS). The ionic liquids were recirculated efficiently.     

Mass spectrometric analysis of androstan-17β-ol-3-one and androstadiene-17β-ol-3-one isomers

Mass spectrometric identification and characterization of steroids using electrospray ionization and tandem mass spectrometry has advantages in drug testing and doping control analysis attributable to limitations of gas chromatography followed by electron ionization mass spectrometry. Steroids with an androstadiene-17beta-ol-3-one nucleus and double bonds located either at C-1 and C-4, C-4 and C-9, or C-4 and C-6 were used to determine characteristic fragmentation pathways. Diagnostic dissociation routes are proposed using deuterium labeling, MS3 experiments, and analyses of structurally closely related compounds. Steroids such as boldenone (androst-1,4-diene-17beta-ol-3-one) produced characteristic product ions at m/z 121, 135, and 147. Compounds with double bonds at C-4 and C-9 generated abundant product ions at m/z 145 and 147. Conjugated double bonds at C-4 and C-6 gave rise to an intense and characteristic signal at m/z 133. Stereochemical differentiation between 5alpha- and 5beta-isomers of androstan-17beta-ol-3-ones was possible because of significant differences in relative abundance of product ions generated by elimination of acetone from alpha,beta-saturated 3-keto steroids.     

Focused ultrasound-assisted acceleration of enzymatic hydrolysis of alkylphenols and 17β-oestradiol glucuronide in fish bile

According to the European Water Framework Directive (WFD), alkylphenols, such as octylphenols and nonylphenols, and 17β-oestradiol are considered as priority or emerging pollutants, respectively, mainly due to their possible properties as endocrine-disrupting compounds (EDCs). EDCs are accumulated in liver, fat, kidney and bile in the glucuronide form. In order to determine the concentration of these compounds in bile, an enzymatic hydrolysis step is necessary. This step is usually long (～16 h), and in this sense, ultrasound probes were studied as a possible alternative energy source to accelerate this process. Enzymatic hydrolysis was reduced to 20 min using an ultrasound probe at one cycle and 10% of amplitude. For validation of analytical procedure, nonylphenol glucuronide (4NP-G), 4-tert-octylphenol glucuronide (4tOP-G) and 4-n-octylphenol glucuronide (4nOP-G) were synthesised while 17β-oestradiol glucuronide (E2-G) was commercially available. Bile from thick-lip grey mullets (Chelon labrosus) was spiked with known amounts of 4NP-G, 4tOP-G, 4nOP-G and E2-G and submitted to the optimised procedure. Good recoveries (77–122%), precision in the 5% to 12% range and limits of detection, ranging from the low nanogramme per gramme level for 4tOP, 4nOP and E2 to the low microgramme per gramme level for nonylphenols, were obtained. The optimised method was applied for the determination of alkylphenol in the bile of thick-lip grey mullets fish bile from the Urdaibai estuary (UNESCO reserve of the Biosphere, Bay of Biscay), and high concentrations (2.3–14.2 μg/g), such as those obtained in polluted areas, were measured. E2 was determined in the bile of thick-lip grey mullets, intraperitoneally injected with E2.     

Structure and magnetic properties of Ho2Co17−xMx pseudobinary compounds

The homogeneity range of the pseudobinary system Ho₂Co_17−xM_x (M ≡; Ni, Fe, Mn, Cr, V, Ti, Cu, Al) and the dependence of the lattice constants and the Curie temperature on composition were studied. Although Ho₂Co₁₇, Ho₂Ni₁₇ and Ho₂Fe₁₇ have identical crystal structures and similar lattice constants, the homogeneity range for the Th₂Ni₁₇-type compound in the Ho₂Co_17−xNi_x and Ho₂Co_17−xFe_x systems is limited to x < 5. The curves of Curie temperature versus composition have maxima at x values of 1, 3 and 0.9 for the systems Ho₂Co_17−xNi_x, Ho₂Co_17−xFe_x and Ho₂Co_17−xCu_x respectively. This suggests that the effect of nickel, iron and copper on the Co-Co exchange interaction in the cobalt sublattice at low concentrations may be different from that at high concentrations.     

Solvent effects on the steady state photophysics of estrone and 17β-estradiol

Absorption and emission yields for estrone and 17β-estradiol were measured in a variety of room temperature solvents. Molar extinction coefficients were found to not vary as a function of solvent, while fluorescence yields were found to be significantly affected by the polarity and hydrogen-bond accepting ability of the solvent, with the yield for 17β-estradiol being highest in nonpolar, hydrogen-bond donating solvents, and lowest in the nonpolar, hydrogen-bond accepting solvent ethyl acetate. Estrone's emission yield was found to be a factor of ten smaller than 17β-estradiol's. Strong solvent and excitation wavelength dependences were found for the relative amounts of emission between estrone's two emission bands, with increased relative emission occurring in nonpolar aprotic solvents, and under higher excitation energies. These results are interpreted with the aid of vertical excitation energies from time-dependent density functional calculations using both explicit and implicit solvation models.     

Density and viscosity of 16α,17α-epoxyprogesterone solutions in chloroform

density and viscosity of 16α,17α-epoxyprogesterone solutions in chloroform were determined over the concentration range up to ∼1.9 mol l⁻¹ at temperatures from 287.65 to 321.15 K. The relative viscosity data were correlated using the extended Jones-Dole equation, a good accuracy of the correlation being obtained.     

SPE and HPLC monitoring of 17-β-estradiol in Egyptian aquatic ecosysetms

Solid-phase extraction and HPLC methods are described for monitoring of 17-β-estradiol residues in Egyptian aquatic ecosystems (water, fish, mollusks, sediment, and drinking water) at the Nile River, Suez Canal region, and northeast of Egypt. Molecular imprinted polymer was prepared and used in extraction. High performance liquid chromatography (HPLC) columns used were Supelcosil C₁₈ and Nucleosil C₁₈. The mobile phases used were different combinations of water and acetonitrile. The concentration of 17-β-estradiol in water, aquatic animals, and sediment samples were of 265.13–7988.12 µg/L, 0.503–96.167, and 0.775–11.884 µg/kg, respectively. Marine lake was contained with high levels of 17-β-estradiol (P < 0.05). Similarly, the Nile River downstream showed high levels of 17-β-estradiol. The detected concentrations in mollusks were significantly higher than those detected in fish. Tilapia fish did not show 17-β-estradiol. Contrarily, low concentrations were detected in the rivulet streams supplied by the Nile River. Besides, 17-β-estradiol was also detected in the sediments at low levels. Detection of 17-β-estradiol in the Egyptian ecosystems attracted attention toward heavy reliance on some esterogenic medicinal products in Egypt. The monitoring of 17-β-estradiol in other water bodies was recommended. Besides, the development of methodologies of bioremediation to eliminate 17-β-estradiol from the Egyptian and other water resources of the world was also suggested.     

Liquid chromatography-tandem mass spectrometry analysis of 17α-trenbolone, 17β-trenbolone and trendione in airborne particulate matter

Trenbolone acetate (TbA) is a potent synthetic anabolic steroid that was approved by the FDA as a growth promoter in beef cattle in 1987. Given the endocrine-modulating activity of TbA and its metabolites in all vertebrates, a sensitive and reliable analytical method is needed to detect TbA and related residues in environmental matrices. We have developed a method that incorporates solid phase extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous determination of the three major TbA metabolites (trendione, 17β-trenbolone, 17α-trenbolone) in total suspended particulate matter (TSP) samples. Sample preparation involved pressurized liquid extraction followed by cleanup on solid-phase extraction cartridges. The procedure was optimized to obtain maximum recovery and minimum signal suppression/enhancement from matrix effects. Analytes were separated with a Phenomenex Gemini-NX C18 analytical column (150 mm × 2.0 mm, 3 μm particle size) using an aqueous methanol gradient at a flow rate of 0.2 mL/min. Column effluent underwent positive electrospray ionization (ESI). Two or more diagnostic product ions were acquired from analyte specific precursor ions for unambiguous confirmation and quantification. The method detection limit was 3.27-4.87 ng/g of particulate matter (PM). Method accuracy, determined with analyte recoveries, ranged between 68% and 117%, and method precision, expressed as relative standard deviation, was below 15% at spiked levels of 6.67, 33.3, and 167 ng/g PM. Analysis of TSP samples demonstrated the presence of the target species associated with PM in the vicinity of beef cattle feeding operations.     

The Conformations of 17β-Estradiol (E2) and 17α-Estradiol as Determined by Solution NMR

The conformational structures of the hormone 17β-estradiol (E2) and the epimeric 17α-estradiol determined by solution NMR spectroscopy and restrained molecular dynamics calculations found a single low energy conformation.     

Catalytic phosphorylation of polyfluoroalkanols. 17. Synthesis and the stereochemistry of tris(α-trifluoromethylbenzyl) phosphates

Catalytic phosphorylation of -trifluoromethylbenzyl alcohols with POCl₃ taken in a ratio of 3 : 1 under particular temperature conditions afforded predominantly symmetrical tris(-trifluoromethylbenzyl) phosphates. The latter were obtained as mixtures of two diastereomers with a statistical ratio of the components.     

Complete chromatographic separation of steroids, including 17α and 17β-estradiols, using a carbazole-based polymeric organic phase in both reversed and normal-phase HPLC

Poly(2-N-carbazolylethyl acrylate) with terminal trimethoxysilyl groups was prepared as an organic phase and immobilized onto silica. The retention behavior of the column packed with this carbazole-based polymer-immobilized silica (Sil-CEA) was investigated by using various estrogenic steroids and corticoids in both reversed-phase and normal-phase liquid chromatography. As a result, complete separation was confirmed for eight kinds of steroids with Sil-CEA. The most specific separation with Sil-CEA can be emphasized by the high separation factor (e.g., α = 1.39 in methanol–water (7:3, v/v) at 35 °C) for 17α and 17β-estradiols, one of the most difficult pairs of isomers in chromatographic separation, whereas for two kinds of commercially available polymeric ODS columns as references α = 1.01, only, under the same conditions. Because the excellent separation and retention order with Sil-CEA was maintained even in a normal-phase mobile phase such as a hexane–2-propanol, it is estimated that the CEA phase has multiple interaction mechanisms through stronger interactions such as dipole–dipole, carbonyl–π, and hydrogen bonding interactions than the hydrophobic effect expected with ODS.     

Conformation Analysis and Comparison of Epristeride(17β-N-t-Butylcarboxamide-androst-3,5-diene-3-carboxylic Acid) and Its Analogs

Conformations of Epristeride(17-β-N-t-butylcarboxamide-androst-3,5-diene-3-carboxylic acid) and its analogs were analyzed with the random search method and compared by means of the methods for steroid conformers, Connolly surfaces, dihedral angles, and molecular accessibility probes with protons, hydroxyl and methyl groups contained simultaneously. Analog d is different from others, which is in accordance with the preliminary clinical trial results under double blind conditions.