- 1,4-Dioxene(2,3-Dihydro-1,4-dioxine) in Organic Synthesis. Part 91. Preparation of Biologically Active Side-Chains From 17-Oxosteroids
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Steroidal (17α-2,3-dihydro-1,4-dioxin-6-yl)-17β-ols of type (2), readily available from 17-oxo steroids and 2,3-dihydro-1,4-dioxine, are easely converted into 21-hydroxy-20-oxo steroids with or without a double bond at the 16(17) position as well as to the dihydroxyacetone side-chain.
- Fetizon, Marcel,Goulaouic, Pierre,Hanna, Issam
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Read Online
- ANTI-CANCER NUCLEAR HORMONE RECEPTOR-TARGETING COMPOUNDS
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The disclosure relates to anti-cancer compounds which are anti-cancer PARP inhibitors of formula Al, A2, A3 or A4 conjugated by a linker to a steroid, whereby the steroid targets the conjugate to the nucleus, as well as to methods for their preparation and use. (I)
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Page/Page column 137-138
(2021/05/21)
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- CYP154C5 Regioselectivity in Steroid Hydroxylation Explored by Substrate Modifications and Protein Engineering**
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CYP154C5 from Nocardia farcinica is a P450 monooxygenase able to hydroxylate a range of steroids with high regio- and stereoselectivity at the 16α-position. Using protein engineering and substrate modifications based on the crystal structure of CYP154C5, an altered regioselectivity of the enzyme in steroid hydroxylation had been achieved. Thus, conversion of progesterone by mutant CYP154C5 F92A resulted in formation of the corresponding 21-hydroxylated product 11-deoxycorticosterone in addition to 16α-hydroxylation. Using MD simulation, this altered regioselectivity appeared to result from an alternative binding mode of the steroid in the active site of mutant F92A. MD simulation further suggested that the entrance of water to the active site caused higher uncoupling in this mutant. Moreover, exclusive 15α-hydroxylation was observed for wild-type CYP154C5 in the conversion of 5α-androstan-3-one, lacking an oxy-functional group at C17. Overall, our data give valuable insight into the structure–function relationship of this cytochrome P450 monooxygenase for steroid hydroxylation.
- Bracco, Paula,Wijma, Hein J.,Nicolai, Bastian,Buitrago, Jhon Alexander Rodriguez,Klünemann, Thomas,Vila, Agustina,Schrepfer, Patrick,Blankenfeldt, Wulf,Janssen, Dick B.,Schallmey, Anett
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p. 1099 - 1110
(2020/12/03)
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- Biotransformation of progesterone by the ascomycete Aspergillus niger N402
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The ability of the ascomyceteAspergillus niger N402 to transform exogenous progesterone was investigated. We found that this strain has steroid-hydroxylating activity and can introduce a hydroxyl group into the progesterone molecule mainly at positions C11(α) and C21 with predominant formation of 21-hydroxyprogesterone (deoxycortone). In addition, formation of 6β,11α-dihydroxyprogesterone was also observed. Studying the effects of the growth medium composition and temperature on progesterone conversion by A. niger N402 showed that the most intense accumulation of 21-hydroxyprogesterone occurred in minimal synthetic medium at 28°C. Increasing the cultivation temperature to 37°C resulted in almost complete inhibition of the hydroxylase activity in the minimal medium. In the complete medium, a similar increase in temperature inhibited 11α-hydroxylase activity and completely suppressed 6β-hydroxylase activity, but it produced no effect on 21-hydroxylating activity.
- Savinova,Solyev,Vasina,Tyazhelova,Fedorova,Savinova
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- Heme-thiolate sulfenylation of human cytochrome P450 4A11 functions as a redox switch for catalytic inhibition
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Cytochrome P450 (P450, CYP) 4A11 is a human fatty acid ω-hydroxylase that catalyzes the oxidation of arachidonic acid to the eicosanoid 20-hydroxyeicosatetraenoic acid (20-HETE), which plays important roles in regulating blood pressure regulation. Variants of P450 4A11 have been associated with high blood pressure and resistance to anti-hypertensive drugs, and 20-HETE has both pro- and antihypertensive properties relating to increased vasoconstriction and natriuresis, respectively. These physiological activities are likely influenced by the redox environment, but the mechanisms are unclear. Here, we found that reducing agents (e.g. dithiothreitol and tris(2-carboxyethyl) phosphine) strongly enhanced the catalytic activity of P450 4A11, but not of 10 other human P450s tested. Conversely, added H2O2 attenuated P450 4A11 catalytic activity. Catalytic roles of five of the potentially eight implicated Cys residues of P450 4A11 were eliminated by site-directed mutagenesis. Using an isotope-coded dimedone/iododimedone-labeling strategy and mass spectrometry of peptides, we demonstrated that the heme-thiolate cysteine (Cys-457) is selectively sulfenylated in an H2O2 concentration-dependent manner. This sulfenylation could be reversed by reducing agents, including dithiothreitol and dithionite. Of note, we observed heme ligand cysteine sulfenylation of P450 4A11 ex vivo in kidneys and livers derived from CYP4A11 transgenic mice. We also detected sulfenylation of murine P450 4a12 and 4b1 heme peptides in kidneys. To our knowledge, reversible oxidation of the heme thiolate has not previously been observed in P450s and may have relevance for 20-HETE-mediated functions.
- Albertolle, Matthew E.,Kim, Donghak,Nagy, Leslie D.,Yun, Chul-Ho,Pozzi, Ambra,Savas, üzen,Johnson, Eric F.,Guengerich, F. Peter
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p. 11230 - 11242
(2017/08/08)
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- Functional analysis of human cytochrome P450 21A2 variants involved in congenital adrenal hyperplasia
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Cytochrome P450 (P450, CYP) 21A2 is the major steroid 21-hydroxylase, converting progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone (17-OH-progesterone) to 11-deoxycortisol. More than 100 CYP21A2 variants give rise to congenital adrenal hyperplasia (CAH). We previously reported a structure ofWT human P450 21A2 with bound progesterone and now present a structure bound to the other substrate (17-OH-progesterone).We found that the 17-OH-progesterone- and progesterone-bound complex structures are highly similar, with only some minor differences in surface loop regions. Twelve P450 21A2 variants associated with either saltwasting or nonclassical forms of CAH were expressed, purified, and analyzed. The catalytic activities of these 12 variants ranged from 0.00009% to 30% of WT P450 21A2 and the extent of heme incorporation from 10% to 95% of the WT. Substrate dissociation constants (Ks) for four variants were 37–13,000-fold higher than for WT P450 21A2. Cytochrome b5, which augments several P450 activities, inhibited P450 21A2 activity. Similar to the WT enzyme, high noncompetitive intermolecular kinetic deuterium isotope effects (> 5.5) were observed for all six P450 21A2 variants examined for 21-hydroxylation of 21-d3- progesterone, indicating that C–H bond breaking is a ratelimiting step over a 104 -fold range of catalytic efficiency. Using UV-visible and CD spectroscopy, we found that P450 21A2 thermal stability assessed in bacterial cells and with purified enzymes differed among salt-wasting- and nonclassical-associated variants, but these differences did not correlate with catalytic activity. Our in-depth investigation of CAH-associated P450 21A2 variants reveals critical insigh into the effects of disease-causing mutations on this important enzyme.
- Wang, Chunxue,Pallan, Pradeep S.,Zhang, Wei,Lei, Li,Yoshimoto, Francis K.,Waterman, Michael R.,Egli, Martin,Guengerich, F. Peter
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p. 10767 - 10778
(2017/07/07)
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- Selective reduction of 4,6- conjugate diene -3-one steroid compound method
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Belonging to the field of chemical pharmacy, the invention relates to a method for selective reduction of 4, 6-conjugated diene-3-one steroid, and solves the problem of low yield in hydrogen reduction. The method mainly includes the steps of: 1) adding the 4, 6-conjugated diene-3-one steroid, a liquid solvent, a catalyst, and a reducing agent hydrogen donor into a reaction kettle, performing nitrogen protection, and carrying out stirring heating till reflux; 2) carry out reflux reaction for 3-10h; 3) at the end of reaction, filtering out the catalyst; 4) distilling the solvent; 5) adding purified water after distillation; and 6) conducting cooling, pumping filtering, washing and drying to obtain a 4-ene-3-steroid crystal.
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Paragraph 0082-0089
(2019/11/21)
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- Human cytochrome P450 21A2, the major steroid 21-hydroxylase: Structure of the enzyme?progesterone substrate complex and rate-limiting C-H bond cleavage
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Cytochrome P450 (P450) 21A2 is the major steroid 21-hydroxylase, and deficiency of this enzyme is involved in ~95% of cases of human congenital adrenal hyperplasia, a disorder of adrenal steroidogenesis. A structure of the bovine enzyme that we published previously (Zhao, B., Lei, L., Kagawa, N., Sundaramoorthy, M., Banerjee, S., Nagy, L. D., Guengerich, F. P., and Waterman, M. R. (2012) Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants. J. Biol. Chem. 287, 10613-10622), containing two molecules of the substrate 17α-hydroxyprogesterone, has been used as a template for understanding genetic deficiencies. We have now obtained a crystal structure of human P450 21A2 in complex with progesterone, a substrate in adrenal 21-hydroxylation. Substrate binding and release were fast for human P450 21A2 with both substrates, and pre-steady-state kinetics showed a partial burst but only with progesterone as substrate and not 17α-hydroxyprogesterone. High intermolecular non-competitive kinetic deuterium isotope effects on both kcat and kcat/Km, from 5 to 11, were observed with both substrates, indicative of rate-limiting C-H bond cleavage and suggesting that the juxtaposition of the C21 carbon in the active site is critical for efficient oxidation. The estimated rate of binding of the substrate progesterone (kon 2.4 × 107 M-1 s-1) is only ~2-fold greater than the catalytic efficiency (kcat/Km = 1.3 × 107 M-1 s-1) with this substrate, suggesting that the rate of substrate binding may also be partially rate-limiting. The structure of the human P450 21A2-substrate complex provides direct insight into mechanistic effects of genetic variants.
- Pallan, Pradeep S.,Wang, Chunxue,Lei, Li,Yoshimoto, Francis K.,Auchus, Richard J.,Waterman, Michael R.,Guengerich, F. Peter,Egli, Martin
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p. 13128 - 13143
(2015/06/02)
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- Regio- and stereoselectivity of P450-catalysed hydroxylation of steroids controlled by laboratory evolution
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A current challenge in synthetic organic chemistry is the development of methods that allow the regio- and stereoselective oxidative C - H activation of natural or synthetic compounds with formation of the corresponding alcohols. Cytochrome P450 enzymes enable C - H activation at non-activated positions, but the simultaneous control of both regio- and stereoselectivity is problematic. Here, we demonstrate that directed evolution using iterative saturation mutagenesis provides a means to solve synthetic problems of this kind. Using P450 BM3(F87A) as the starting enzyme and testosterone as the substrate, which results in a 1:1 mixture of the 2β- and 15β-alcohols, mutants were obtained that are 96 - 97% selective for either of the two regioisomers, each with complete diastereoselectivity. The mutants can be used for selective oxidative hydroxylation of other steroids without performing additional mutagenesis experiments. Molecular dynamics simulations and docking experiments shed light on the origin of regio- and stereoselectivity.
- Kille, Sabrina,Zilly, Felipe E.,Acevedo, Juan P.,Reetz, Manfred T.
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scheme or table
p. 738 - 743
(2012/02/15)
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- Aspects of the progesterone response in Hortaea werneckii: Steroid detoxification, protein induction and remodelling of the cell wall
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Progesterone in sublethal concentrations temporarily inhibits growth of Hortaea werneckii. This study investigates some of the compensatory mechanisms which are activated in the presence of progesterone and are most probably contributing to escape from growth inhibition. These mechanisms lead on the one hand to progesterone biotransformation/detoxification but, on the other, are suggested to increase the resistance of H. werneckii to the steroid. Biotransformation can detoxify progesterone efficiently in the early logarithmic phase, with mostly inducible steroid transforming enzymes, while progesterone biotransformation/detoxification in the late logarithmic and stationary phases of growth is not very efficient. The relative contribution of constitutive steroid transforming enzymes to progesterone biotransformation is increased in these latter phases of growth. In the presence of progesterone, activation of the cell wall integrity pathway is suggested by the overexpression of Pck2 which was detected in the stationary as well as the logarithmic phase of growth of the yeast. Progesterone treated H. werneckii cells were found to be more resistant to cell lysis than mock treated cells, indicating for the first time changes in the yeast cell wall as a result of treatment with progesterone.
- Krizancic Bombek, Lidija,Lapornik, Ajda,Ukmar, Marjeta,Matis, Maja,Cresnar, Bronislava,Katalinic, Jasna Peter,Zakelj-Mavric, Marija
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experimental part
p. 1465 - 1474
(2009/04/06)
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- Biotransformation of progesterone by the green alga Chlorella emersonii C211-8H
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2β-Hydroxyprogesterone, 6β-hydroxyprogesterone, 9α-hydroxyprogesterone, 14α-hydroxyprogesterone, 16α-hydroxyprogesterone and 21-hydroxyprogesterone are the main bioproducts in the progesterone bioconversion by axenic cultures of Chlorella emersonii C211-8
- Della Greca, Marina,Fiorentino, Antonio,Pinto, Gabriele,Pollio, Antonino,Previtera, Lucio
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p. 1527 - 1529
(2007/10/03)
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- Biotransformations of progesterone by Chlorella spp.
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Thirty-eight strains of Chlorella spp. were used as bioreactors on progesterone. Fourteen strains were ineffective whilst the others biotransformed the substrate. The observed bioreactions for progesterone were the hydroxylation, the reduction and the side-chain degradation. The kinds of biotransformation seem to fit the actual classification of the strains.
- Pollio, Antonino,Pinto, Gabriele,Della Greca, Marina,Fiorentino, Antonio,Previtera, Lucio
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p. 685 - 688
(2007/10/03)
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- Synthesis of 17-(2-Methoxy-3-oxazolin-4-yl)-, 17-(3-Oxazolin-4-yl)-, and 17-(2-Oxazolin-4-ylidene)-Substituted Steroids and Their Use as Precursors of Corticosteroids
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17-(Isocyanotosylmethylene)steroids 4 are useful intermediates in the conversion of 17-oxosteroids into 17-(hydroxyacetyl)steroids.The 21-CH2OH group is effectively introduced by a base-mediated reaction of compounds 4 with formaldehyde and MeOH to give 17-(2-methoxy-3-oxazolin-4-yl)derivatives 12, which by acid hydrolysis give 17-(hydroxyacetyl)steroids 10 and 16 in high yields.Partial hydrolysis of the same oxazoline derivatives 12 provides the 17-(hydroxyacetyl) cortico side chain of 13 equipped with a formyl-protected hydroxy group. 3-Oxazolinyl and 2-oxazolinylidene steroid derivatives 19, 20, and 21, without a 2-methoxy substituent, are discussed as alternatives of 12.
- Leusen, Daan van,Batist, Jacobus N. M.,Lei, Jia,Echten, Erik van,Brouwer, Antoon C.,Leusen, Albert M. van
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p. 5650 - 5657
(2007/10/02)
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- Efficient C-21 Deoxygenation of 21-Alkoxy-20-keto Corticoid Steroids with Trimethylsilyl Iodide in the Presence of Methanol
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Reaction of 21-alkyl ethers 1, 4-6, 8, and 9 with a large excess of trimethylsilyl iodide (TMSI) produced the deoxygenated products 3 and 11 in low to moderate yields along with a small amount of 21-alcohols 2 and 10.The deoxygenation reaction in the presence of 1.5 molar equiv of MeOH gave the products in much higher yields than those without MeOH, except the reaction of the ethyl and n-propyl ethers 4 and 5.Treatment of 1 and 8 with trimethylsilyl chloride/NaI in the presence of MeOH gave similar results to those with TMSI.Compound 3 was also produced in high yields by reaction of 1 and 4 with HI under mild conditions.On the other hand, treatment of 17α-ketol 7 with TMSI in the presence of MeOH yielded 17aβ-methyl D-homo steroid 15.The results along with deuterium-labeling experiments with MeOD and IR and 1H NMR spectral analysis during the reaction with TMSI suggest that dealkylation of the 21-alkyl ethers precedes the deoxygenation, in which HI produced in situ by reaction of MeOH with TMSI would be involved.
- Nagaoka, Masao,Kunitama, Yurie,Numazawa, Mitsuteru
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p. 334 - 338
(2007/10/02)
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- BIOSYNTHESIS OF ANDROGENS BY PHEOCHROMOCYTOMAS
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Homogenates from four adrenal pheochromocytomas converted 4-14C-labeled pregnenolone, 17-hydroxyprogesterone, and dehydroepiandrosterone into androstenedione and testosterone.In addition to these androgens, labeled pregnane substrates were also transformed into corticosteroids, as previously reported, and this conversion occurred in even higher yield.The formation of labeled metabolites of either pathway was greater in homogenates from intraadrenal pheochromocytomas than in those derived from an extraadrenal tumor, but less than in preparations of hyperplastic adrenal cortex.Incubations of subcellular fractions isolated from an adrenal pheochromocytoma showed that the enzyme activities involved in androgen formation from the radioactive substrates studied were associated with the microsomes and required exogenous cofactors.In contrast to adrenocortical tissue, chromaffin cell preparations uniformly failed to convert substrate cholesterol into either androgens or corticosteroids.The data available demonstrate the presence in chromaffin tissue of all of the enzyme activities required for the biosynthesis of androgens and corticosteroids except for those involved in the side-chain scission of cholesterol.
- Carballeira, Andres,Brown, John W.,Fishman, Lawrence M.
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p. 647 - 660
(2007/10/02)
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- New Synthesis of the Corticosterone Side-Chain
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Condensation reactions between azlactone 2 and 17-ketosteroids 1 followed by opening of the azlactone ring with sodium methanolate yields methyl 20-benzoylamino-17(20)-pregnen-21-oates 6.Reduction of the ester and subsequent hydrolysis produce compounds with the corticosterone side-chain as well as a ring-closed product of new type.
- Solyom, Sandor,Szilagyi, Katalin,Toldy, Lajos
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p. 153 - 160
(2007/10/02)
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- Novel 20 benzcylamino pregnene derivatives and process for preparing same
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The invention relates to new pregnene derivatives of the general formula (I), STR1 wherein R1 stands for a C1-4 alkyl group; R2 stands for a hydrogen atom or a C2-4 alkanoyl group; R3 stands for a hydrogen atom, a hydroxyl group or a C2-4 alkanoyloxy group; A represents a ring of the general formula (1) STR2 or a ring of the general formula (2), STR3 wherein R4 means a hydrogen atom or a methyl group; R5 stands for a hydroxyl group, a C2-4 alkanoyloxy group or a C1-3 alkoxy group; R6 means a hydroxyl group, a C2-4 alkanoyloxy group, a C1-3 alkoxy group, an oxo group or a C2-3 alkylenedithio group; the dotted line optionally represents one or more additional valence bonds, with the proviso that, when the dotted line between C9 and C11 represents an additional valence bond, then R3 stands for a hydrogen atom; and the wavy line shows that the given substituent can be bound to the carbon atom in two alternative spatial arrangements, as well as to their stereoisomers and the mixture of these stereoisomers. The compounds of the general formula (I) are valuable intermediates for the synthesis of known biologically active 21-hydroxyprogesterone derivatives.
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- New Preparation and Controlled Alkaline Hydrolysis of 21-Bromo-20-ketopregnenes. A Facile Synthesis of Deoxycorticoids
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Syntheses of deoxycorticoids 7b, 8b, and 9b are described.Treatment of 20-oxo steroid 1 with 3 mol equiv of CuBr2 in MeOH in the presence or absence of pyridine gave the 21-bromide 4a or the 17α-methoxide 2 in high yields, respectively.When 6 mol equiv of the brominating reagent was used in the absence of pyridine, the 21-bromo-17α-methoxide 5a was formed. 17α-hydroxy 20-ones 3 could be similarly converted to the 21-bromides 6a and 6b.Oxidation of 4a, 5a, and 6a with CrO3 and subsequent isomerization of a double bond at C-5 with acid gave the corresponding 4-ene-3-ones 7a, 8a, and 9a, of which 7a and 9a were efficiently hydrolized to 7b and 9b under controlled conditions with a K2CO3-H2O-acetone system.On the other hand, 8a was converted to 8b by reaction with NaOCH3 in MeOH.
- Numazawa, Mitsuteru,Nagaoka, Masao
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- 17-[(Hydroxymethyl)formamido-methylene]-steroids
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Novel 17-[(hydroxymethyl)formamido methylene]-steroids of the formula STR1 wherein R1 is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms optionally substituted with halogen or an oxygen or nitrogen function and alkenyl and alkynyl of 2 to 4 carbon atoms, R2 is alkyl of 1 to 4 carbon atoms and the A,B,C and D rings may contain one or more double bonds and are optionally substituted with at least one member of the group consisting of hydroxy, keto, halogen, alkyl and alkoxy of 1 to 4 carbon atoms and alkenyl and alkynyl of 2 to 4 carbon atoms and a process for their preparation which are intermediates for the preparation of the corresponding 17-hydroxyacetyl steroids.
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- Water-soluble steroid compounds
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Beta-cyclodextrin forms a water-soluble complex or inclusion compound with steroid compounds having a molecular structure smaller than the interior cavity in the doughnut-shaped molecular structure of beta-cyclodextrin. The resulting inclusion compounds can be used for a variety of applications including aqueous topical ophthalmic preparations and topical dermatological ointments.
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- Cytotoxic nucleoside-corticosteroid phosphodiesters
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Nucleotides of nucleosides or bases having known cytotoxic activity are reacted with steroids, preferably corticosteroids, to form corresponding cytotoxic nucleoside-corticosteroid phosphodiester analogues of the formula: STR1 wherein: steroid is the residue formed by removal of a hydroxyl hydrogen atom from a natural or synthetic adrenal corticosteroid containing the characteristic cyclopentanophenanthrene nucleus which is esterified to the phosphate moiety at the 21-position; sugar is a naturally occurring pentose or deoxypentose in the furanose form, preferably ribose, deoxyribose, lyxose, xylose or arabinose and especially ribose, deoxyribose or arabinose, which is esterified to the phosphate moiety at the 5'-position and covalently bonded to the heterocycle moiety at the 1'-position to form a nucleoside; and heterocycle is a purine, pyrimidine, hydrogenated pyrimidine, triazolopurine or similar nucleoside base. The conjugates exhibit an enhanced therapeutic index as compared to the parent nucleoside or base compounds, and are thus useful cytotoxic, antiviral and antineoplastic agents.
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- Differences between adrenal adenoma causing primary aldosteronism and other adrenal tissues in the incorporation of labeled steroid precursors into their products
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The incorporation and conversion of several labeled steroid precursors into their products were examined in slices of adrenal tissue from two patients with primary aldosteronism and compared with that in 'normal' adrenal tissue and adrenal tissues from a patient with Cushing's syndrome. The products of the incorporation were separated by Sephadex LH-20 column chromatography. The major products of conversion in the adenomatous tissue of primary aldosteronism were 18-hydroxycorticosterone and lesser amounts of aldosterone. Smaller amounts of 18-hydroxycorticosterone were isolated from all other adrenal tissues studied. No aldosterone could be recovered after incubating any of the adrenal tissue studied with labeled 18-hydroxy-11-deoxycorticosterone or 18-hydroxycorticosterone as precursor steroid. These in vitro results seem to suggest that there is increased 18-hydroxylation in the adenoma of primary aldosteronism compared with other tissues and that relatively more 18-hydroxycorticosterone is produced in such tissue than aldosterone.
- Usa,Ganguly,Weinberger
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p. 531 - 545
(2007/10/02)
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- Selenium-75 steroids
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Novel dimeric and monomeric selenium-75 derivatives of steroids are made by reacting a keto steroid with selenium-75 dioxide or selenious acid-Se75. The resulting diselenide dimers can be converted into monomeric compounds by the use of a cleaving reagent followed by an alkylating agent. The compounds are useful in saturation analyses such as radioimmunoassays.
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- Novel N-nitroso compounds, compositions containing such compounds, processes for their preparation and methods of treatment therewith, and novel intermediates
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This invention relates to novel N-halogenoalkyl-N-nitroso carbamates and N 4 halogenalkyl-N 4 -nitroso allophanates of steroid compounds, having an anti-tumor activity, and to the preparation thereof. The invention is also concerned with pharmaceutical compositions containing the said compounds, and methods of treatment therewith.
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