- Mechanism of the hydrolysis of the sulfamate EMATE-an irreversible steroid sulfatase inhibitor
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The kinetics of hydrolysis of the medicinally important sulfamate ester EMATE have been probed over a wide pH range and into moderately strong base (H_ region). Analysis of the pH/H_-rate profile, measurements of pKas, solvent-reactivity, kinetic isotope effects and determination of activation data reveal that in the pH range from ～1 to ～8 an SN2 (S) solvolytic mechanism is followed and after the pKa of EMATE (pKa ～9) is passed, a second pathway showing a first-order dependence on base operates and an E1cB mechanism is supported.
- Spillane, William J.,Malaubier, Jean-Baptiste
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- Characterization of 17β-hydroxysteroid dehydrogenase and regulators involved in estrogen degradation in Pseudomonas putida SJTE-1
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In bacteria, the enzyme catalyzing the transformation of 17β-estradiol is considered the key enzyme for its metabolism, whose enzymatic activity and regulatory network influence the biodegradation efficiency of this typical estrogen. In this work, a novel 17β-hydroxysteroid dehydrogenase (17β-HSD) was characterized from the estrogen-degrading strain Pseudomonas putida SJTE-1, and two regulators were identified. This 17β-HSD, a member of the short-chain dehydrogenase/reductase (SDR) superfamily, could be induced by 17β-estradiol and catalyzed the oxidization reaction at the C17 site of 17β-estradiol efficiently. Its Km value was 0.068?mM, and its Vmax value was 56.26?μmol/min/mg; over 98% of 17β-estradiol was oxidized into estrone in 5?min, indicating higher efficiency than other reported bacterial 17β-HSDs. Furthermore, two genes (crgA and oxyR) adjacent to 17β-hsd were studied which encoded the potential CrgA and OxyR regulators. Overexpression of crgA could enhance the transcription of 17β-hsd, while that of oxyR resulted in the opposite effect. They could bind to the specific and different sites in the promoter region of 17β-hsd gene directly, and binding of OxyR could be released by 17β-estradiol. OxyR repressed the expression of 17β-hsd by its specific binding to the conserved motif of GATA-N9-TATC, while CrgA activated the expression of this gene through its binding to the motif of T-N11-A. Therefore, this 17β-HSD transformed 17β-estradiol efficiently and the two regulators regulated its expression directly. This work could promote the study of the enzymatic mechanism and regulatory network of the estrogen biodegradation pathway in bacteria.
- Wang, Pingping,Zheng, Daning,Peng, Wanli,Wang, Yanqiu,Wang, Xiuli,Xiong, Weiliang,Liang, Rubing
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- Synthetic approaches towards 4-functionalized estrone derivatives
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Directed ortho-lithiation of estrone carbamate followed by reaction with electrophiles afforded 2-substituted estrone derivatives. Reductive cleavage of the carbamate group followed by O-allylation and Claisen rearrangement led to new 4-functionalized est
- Schoen, Uwe,Messinger, Josef,Solodenko, Wladimir,Kirschning, Andreas
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Read Online
- The Status of Oxygen Atoms in the Removal of C-19 in Oestrogen Biosynthesis
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Three O2-dependent reactions are involved in the removal of C-19 as formate, in oestrogen biosynthesis; it is shown that the oxygen atoms introduced in steps 1 and 3 of the process are the ones which are found in the biosynthetic formate.
- Akhtar, Muhammed,Calder, Michael R.,Corina, David L.,Wright, J. Neville
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Read Online
- An efficient steroid pharmacophore-based strategy to identify new aromatase inhibitors
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Aromatase, an enzyme involved in the conversion of androgens into estrogens, is an important target for the endocrine treatment of breast cancer. Aromatase inhibition is usually achieved with steroids structurally related to the substrate of catalysis or,
- Neves, Marco A.C.,Dinis, Teresa C.P.,Colombo, Giorgio,Sa e Melo, M. Luisa
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Read Online
- Gold nanoparticles as dehydrogenase mimicking nanozymes for estradiol degradation
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Nanozyme catalysis has been mainly focused on a few chromogenic and fluorogenic substrates, while environmentally and biologically important compounds need to be tested to advance the field. In this work, we studied oxidation of estradiol (E2) in the presence of various nanomaterials including gold nanoparticles (AuNPs), nanoceria (CeO2), Fe3O4, Fe2O3, MnO2 and Mn2O3, and found that AuNPs had a dehydrogenase-mimicking activity to convert E2 to estrone (E1). This conversion was monitored using HPLC. The reaction was faster at higher pH and reached saturation at pH 8. Smaller AuNPs had a higher catalytic efficiency and 5 nm AuNPs were 4.8-fold faster than 13 nm at the same total surface area. Finally, we tried 17α-ethinylestradiol (EE2) as a substrate and found that 5 nm AuNPs can catalyze EE2 oxidation in the presence of H2O2. This work indicated that some nanomaterials can affect environmentally important hormones via oxidation reactions, and this study has expanded the scope of substrate of nanozymes.
- Zhang,Bragg, Leslie M.,Servos, Mark R.,Liu, Juewen
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Read Online
- Me3SI-promoted chemoselective deacetylation: a general and mild protocol
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A Me3SI-mediated simple and efficient protocol for the chemoselective deprotection of acetyl groups has been developedviaemploying KMnO4as an additive. This chemoselective deacetylation is amenable to a wide range of substrates, tolerating diverse and sensitive functional groups in carbohydrates, amino acids, natural products, heterocycles, and general scaffolds. The protocol is attractive because it uses an environmentally benign reagent system to perform quantitative and clean transformations under ambient conditions.
- Gurawa, Aakanksha,Kashyap, Sudhir,Kumar, Manoj
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p. 19310 - 19315
(2021/06/03)
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- Catalytic SNAr Hydroxylation and Alkoxylation of Aryl Fluorides
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Nucleophilic aromatic substitution (SNAr) is a powerful strategy for incorporating a heteroatom into an aromatic ring by displacement of a leaving group with a nucleophile, but this method is limited to electron-deficient arenes. We have now established a reliable method for accessing phenols and phenyl alkyl ethers via catalytic SNAr reactions. The method is applicable to a broad array of electron-rich and neutral aryl fluorides, which are inert under classical SNAr conditions. Although the mechanism of SNAr reactions involving metal arene complexes is hypothesized to involve a stepwise pathway (addition followed by elimination), experimental data that support this hypothesis is still under exploration. Mechanistic studies and DFT calculations suggest either a stepwise or stepwise-like energy profile. Notably, we isolated a rhodium η5-cyclohexadienyl complex intermediate with an sp3-hybridized carbon bearing both a nucleophile and a leaving group.
- Kang, Qi-Kai,Li, Ke,Li, Yuntong,Lin, Yunzhi,Shi, Hang,Xu, Lun
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supporting information
p. 20391 - 20399
(2021/08/13)
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- PhIO-Mediated oxidative dethioacetalization/dethioketalization under water-free conditions
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Treatment of thioacetals and thioketals with iodosobenzene in anhydrous DCM conveniently afforded the corresponding carbonyl compounds in high yields under water-free conditions. The mechanistic studies indicate that this dethioacetalization/dethioketalization process does not need water and the oxygen of the carbonyl products comes from the hypervalent iodine reagent.
- Du, Yunfei,Ouyang, Yaxin,Wang, Xi,Wang, Xiaofan,Yu, Zhenyang,Zhao, Bingyue,Zhao, Kang
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- Photochemical Behavior of Some Estrone Aryl and Methyl Sulfonates in Solution: Preparative and Mechanistic Studies
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Direct irradiation of estrone aryl and methyl sulfonates in different organic solvents under nitrogen atmosphere was investigated under steady-state conditions. The estrone derivatives reacted efficiently through the photo-Fries rearrangement reaction involving [1;3]-sulfonyl migration providing the ortho-sulfonyl estrone derivatives and estrone as the photoproducts. In addition, estrone and 2-arylsulfonyl estrone derivatives were epimerized involving a Norrish Type-I reaction. Chemical quenching and photosensitization experiments on the photoreaction have been also carried out to establish the photoreactive excited state. Likewise, the solvent effect and the nature of the sulfonyl group on the photoreactions have been also studied.
- Quindt, Matías I.,Gola, Gabriel F.,Ramirez, Javier A.,Bonesi, Sergio M.
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- Solvent- and Wavelength-Dependent Photolysis of Estrone
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The direct photolysis of estrone in solvents ranging from water to cyclohexane is reported. The photodegradation is dominated by lumiestrone, an epimer of estrone resulting from the inversion of the methyl group at carbon 13, regardless of solvent and pho
- Adriano, Natalie,Ahearn, Ceilidh,Black, Cory,Cracchiolo, Michael,Ghere, Daniel,Hare, Patrick M.,Nu?ez, Alexandra,Olivan, Lars,Patel, Raj,Saner, Stephanie,Smith, Krista R.,Watkins, Barbie
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- Bimetallic photoredox catalysis: Visible light-promoted aerobic hydroxylation of arylboronic acids with a dirhodium(ii) catalyst
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We report the use of a rhodium(II) dimer in visible light photoredox catalysis for the aerobic oxidation of arylboronic acids to phenols under mild conditions. Spectroscopic and computational studies indicate that the catalyst Rh2(bpy)2(OAc)4 (1) undergoes metal-metal to ligand charge transfer upon visible light irradiation, which is responsible for catalytic activity. Further reactivity studies demonstrate that 1 is a general photoredox catalyst for diverse oxidation reactions.
- Campbell, Michael G.,Chuang, Gary Jing,Liu, Ming-Lun,Miura-Stempel, Emily,Tu, Jing-Wen,Yang, Hsiang-Ming
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p. 2040 - 2047
(2020/03/13)
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- Base-free oxidation of alcohols enabled by nickel(ii)-catalyzed transfer dehydrogenation
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An efficient nickel(ii)-catalyzed transfer dehydrogenation oxidation of alcohols is reported that relies on cyclohexanone as the formal oxidant and does not require the use of an external base. The synthetic utility of this protocol is demonstratedviathe facile oxidation of structurally complicated natural products.
- Ye, Danfeng,Liu, Zhiyuan,Sessler, Jonathan L.,Lei, Chuanhu
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supporting information
p. 11811 - 11814
(2020/10/13)
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- Reductive Aromatization of Quinols with B2pin2 as Deoxidizing Agent
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We have demonstrated B2pin2 as superior deoxidizing agent for the reductive deoxygenation of quinol derivatives under basic conditions. A wide range of highly functionalized phenols were obtained in good yields including a complex drug molecule, which revealed the high functional group tolerance of this protocol.
- Liu, Bin,Xu, Yin,Luo, Zhibin,Xie, Jimin
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supporting information
p. 1022 - 1024
(2020/03/19)
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- Total synthesis preparation method of estrone
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The invention relates to the technical field of bulk drug manufacturing, and particularly discloses a total synthesis preparation method of estrone. According to the preparation method, estrone is obtained by using tetralone as a starting raw material through seven chemical synthesis steps of Grignard reaction, hydrolysis, condensation, cyclization, ketal protection, hydrogenation and hydrolysis.According to the invention, the preparation method has characteristics of easily available raw materials, simple reaction route, mild reaction conditions, high stereoselectivity, low pollution, low cost and good application prospects.
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- Pd-catalyzed Suzuki–Miyaura couplings and evaluation of 13α-estrone derivatives as potential anticancer agents
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13α-Estrones are of great value owing to their potent multiple bioactivity, including anticancer activity. 3-OH or 3-OBn derivatives of 2- or 4-[(subst.) phenyl]-13α-estrone as potential antiproliferative agents have been synthesized via facile, microwave
- Ali, Hazhmat,Horváth, Gergely,Jójárt, Rebeka,Kele, Zoltán,Mernyák, Erzsébet,Zupkó, István
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- Comprehensive kinetic and substrate specificity analysis of an arylsulfatase from Helix pomatia using mass spectrometry
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Sulfatases hydrolyze sulfated metabolites to their corresponding alcohols and are present in all domains of life. These enzymes have found major application in metabolic investigation of drugs, doping control analysis and recently in metabolomics. Interest in sulfatases has increased due to a link between metabolic processes involving sulfated metabolites and pathophysiological conditions in humans. Herein, we present the first comprehensive substrate specificity and kinetic analysis of the most commonly used arylsulfatase extracted from the snail Helix pomatia. In the past, this enzyme has been used in the form of a crude mixture of enzymes, however, recently we have purified this sulfatase for a new application in metabolomics-driven discovery of sulfated metabolites. To evaluate the substrate specificity of this promiscuous sulfatase, we have synthesized a series of new sulfated metabolites of diverse structure and employed a mass spectrometric assay for kinetic substrate hydrolysis evaluation. Our analysis of the purified enzyme revealed that the sulfatase has a strong preference for metabolites with a bi- or tricyclic aromatic scaffold and to a lesser extent for monocyclic aromatic phenols. This metabolite library and mass spectrometric method can be applied for the characterization of other sulfatases from humans and gut microbiota to investigate their involvement in disease development.
- Correia, Mário S.P.,Ballet, Caroline,Meistermann, Hannes,Conway, Louis P.,Globisch, Daniel
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p. 955 - 962
(2019/02/09)
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- Tetrafluoropyridyl (TFP): a general phenol protecting group readily cleaved under mild conditions
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Phenols are extremely valuable building blocks in the areas of pharmaceuticals, natural products, materials and catalysts. In order to carry out modifications on phenols, the phenolic oxygen is routinely protected to prevent unwanted side reactions. Presently many of the protecting groups available can require harsh conditions, specialist equipment, expensive or air/moisture-sensitive reagents to install and remove. Here we introduce the use of the tetrafluoropyridyl (TFP) group as a general protecting group for phenols. TFP can be installed in one step with no sensitivity to water or air, and it is stable under a range of commonly employed reaction conditions including acid and base. The TFP protecting group is readily cleaved under mild conditions with quantitative conversion to the parent phenol, observed in many cases in less than 1 hour.
- Brittain, William D. G.,Cobb, Steven L.
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supporting information
p. 2110 - 2115
(2019/02/27)
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- Photo-Fries Rearrangement of Some 3-Acylestrones in Homogeneous Media: Preparative and Mechanistic Studies
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Irradiation of a series of 3-acylestrones under a nitrogen atmosphere in cyclohexane, acetonitrile (MeCN), and methanol (MeOH) was investigated under steady-state conditions. The molecules underwent the photo-Fries rearrangement, with concomitant homolytic fragmentation of the ester group and [1;3]-acyl migration. This pathway afforded the ortho-acyl estrone derivatives, the main photoproducts, together with estrone. During the irradiation of 3-benzoyl estrone, epimerization of estrone through the Norrish type I reaction occurred, providing lumiestrone as the photoproduct. This photoreaction involves the fragmentation of the C-α at the carbonyl group (C-17) of the steroid. On the other hand, epimerization of ortho-regioisomer 2-acetyl estrone occurred during the irradiation of 3-acetyl estrone. Photosensitization with acetone and chemical quenching with N,N,N,N-tetramethyldiazetinedioxide of the photo-Fries reaction confirmed that the photoreaction took place from the singlet excited state while the Norrish type I reaction proceeds efficiently from the triplet excited state. Solvent effects, as well as the nature of the acyl group on the photoreactions, were also studied.
- Quindt, Matías I.,Gola, Gabriel F.,Ramirez, Javier A.,Bonesi, Sergio M.
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p. 7051 - 7065
(2019/06/18)
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- Synthesis method of estrone
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The invention discloses a synthesis method of estrone. The synthesis method comprises the following steps: in an organic solvent, performing an aromatization reaction of a compound 2, an organic phosphine reagent and halogen to obtain a compound 1. The synthesis method disclosed by the invention has the advantages of easiness in operation, mild conditions and high yield; by adopting the method disclosed by the invention to synthesize estrone, the yield can reach 70%, and a feasible way is provided for the estrone synthesis technology.
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Paragraph 0025; 0026; 0027; 0028; 0029; 0030; 0031-0045
(2018/03/28)
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- New enzymatic and mass spectrometric methodology for the selective investigation of gut microbiota-derived metabolites
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Gut microbiota significantly impact human physiology through metabolic interaction. Selective investigation of the co-metabolism of bacteria and their human host is a challenging task and methods for their analysis are limited. One class of metabolites associated with this co-metabolism are O-sulfated compounds. Herein, we describe the development of a new enzymatic assay for the selective mass spectrometric investigation of this phase II modification class. Analysis of human urine and fecal samples resulted in the detection of 206 sulfated metabolites, which is three times more than reported in the Human Metabolome Database. We confirmed the chemical structure of 36 sulfated metabolites including unknown and commonly reported microbiota-derived sulfated metabolites using synthesized internal standards and mass spectrometric fragmentation experiments. Our findings demonstrate that enzymatic sample pre-treatment combined with state-of-the-art metabolomics analysis represents a new and efficient strategy for the discovery of unknown microbiota-derived metabolites in human samples. Our described approach can be adapted for the targeted investigation of other metabolite classes as well as the discovery of biomarkers for diseases affected by microbiota.
- Ballet, Caroline,Correia, Mário S. P.,Conway, Louis P.,Locher, Theresa L.,Lehmann, Laura C.,Garg, Neeraj,Vujasinovic, Miroslav,Deindl, Sebastian,L?hr, J.-Matthias,Globisch, Daniel
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p. 6233 - 6239
(2018/08/07)
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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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- DEHYDROGENATION CATALYST, AND CARBONYL COMPOUND AND HYDROGEN PRODUCTION METHOD USING SAID CATALYST
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Objects of the present invention are to provide a novel dehydrogenation reaction catalyst, to provide a method that can produce a ketone, an aldehyde, and a carboxylic acid with high efficiency from an alcohol, and to provide a method for efficiently producing hydrogen from an alcohol, formic acid, or a formate, and they are accomplished by a catalyst containing an organometallic compound of Formula (1).
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Paragraph 0145
(2016/10/31)
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- Thermodynamic Meerwein-Ponndorf-Verley reduction in the diastereoselective synthesis of 17α-estradiol
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The synthesis of 17α-hydroxy steroids generally requires multiple synthetic manipulations. The synthesis of 17α-estradiol is no exception, as this process involves the protection and release of the 3-hydroxy functional group. The diastereoselective reduction of the 17-keto-steroid can be utilized to prepare 17α-hydroxy-steroids. Here, 17α-estradiol was synthesized from commercially available estrone under thermodynamic Meerwein-Ponndorf-Verley (MPV) conditions in a single step, followed by simple chromatographic separation over silica gel. The remaining mixture of unreacted estrone and estradiols was easily recycled through Oppenauer oxidation to estrone, with an overall yield of 68% 17α-estradiol.
- Ahmed, Gulzar,Nickisch, Klaus
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- Eco-friendly synthesis of 3-etherified estrones
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The conventional etherification uses toxic or hardly degradable alkylating agents. An eco-friendly tandem etherification/aromatization is presented to prepare estrone 3-secondary ethers from easily available dienone 1. Three marketed 3-etherified estrogen drugs were synthesized with the method from commercial available starting material.
- Zheng, Dong-Qing,Jing, Yu,Zheng, Bing-Ying,Ye, Yun-Fei,Xu, Sheng,Tian, Wei-Sheng,Ma, Hai-Yan,Ding, Kai
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p. 2164 - 2169
(2016/04/09)
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- Thermodynamic evaluation of aromatic CH/π interactions and rotational entropy in a molecular rotor
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A molecular rotor built with a stator formed by two rigid 9β-mestranol units having a 90° bent angle linked to a central phenylene rotator has an ideal structure to examine aromatic CH/π interactions. Energies and populations of the multiple solution conformations from quantum-mechanical calculations and molecular dynamics simulations were combined with variable-temperature (VT) 1H NMR data to establish the enthalpy of this interaction and the entropy associated with rotation about a single bond. Rotational dynamics in the solid state were determined via VT cross-polarization magic-angle spinning 13C NMR spectroscopy.
- Prez-Estrada, Salvador,Rodrguez-Molina, Braulio,Xiao, Leilei,Santillan, Rosa,Jimnez-Oss, Gonzalo,Houk,Garcia-Garibay, Miguel A.
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p. 2175 - 2178
(2015/03/04)
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- CATALYST FOR DEHYDROGENATION, AND MANUFACTURING METHOD OF CARBONYL COMPOUND AND HYDROGEN USING THE CATALYST
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PROBLEM TO BE SOLVED: To provide a novel catalyst for dehydrogenation, a method for manufacturing ketone, aldehyde and carboxylic acid from alcohols by using the catalyst at high efficiency, and a method for efficiently manufacturing hydrogen from formic acid and formate. SOLUTION: There is provided a catalyst containing the formula (1), where Ar is benzene which may have a substituent or a cyclopentadienyl group which may have a substituent and M represents ruthenium, rhodium or iridium, e.g. an organic metal compound represented by Compounds 1 and 2. COPYRIGHT: (C)2015,JPO&INPIT
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Paragraph 0099
(2017/01/02)
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- Aldo-keto Reductase 1B15 (AKR1B15): A mitochondrial human aldo-keto reductase with activity toward steroids and 3-keto-acyl-CoA conjugates
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Alto-keto reductases (AKRs) comprise a superfamily of proteins involved in the reduction and oxidation of biogenic and xenobiotic carbonyls. In humans, at least 15 AKR superfamily members have been identified so far. One of these is a newly identified gene locus, AKR1B15, which clusters on chromosome 7 with the other human AKR1B subfamily members (i.e. AKR1B1 and AKR1B10). We show that alternative splicing of the AKR1B15 gene transcript gives rise to two protein isoforms with different N termini: AKR1B15.1 is a 316-amino acid protein with 91% amino acid identity to AKR1B10; AKR1B15.2 has a prolonged N terminus and consists of 344 amino acid residues. The two gene products differ in their expression level, subcellular localization, and activity. In contrast with other AKR enzymes, which are mostly cytosolic, AKR1B15.1 co-localizes with the mitochondria. Kinetic studies show that AKR1B15.1 is predominantly a reductive enzyme that catalyzes the reduction of androgens and estrogens with high positional selectivity (17β-hydroxysteroid dehydrogenase activity) as well as 3-ketoacyl-CoA conjugates and exhibits strong cofactor selectivity toward NADP(H). In accordance with its substrate spectrum, the enzyme is expressed at the highest levels in steroid-sensitive tissues, namely placenta, testis, and adipose tissue. Placental and adipose expression could be reproduced in the BeWo and SGBS cell lines, respectively. In contrast, AKR1B15.2 localizes to the cytosol and displays no enzymatic activity with the substrates tested. Collectively, these results demonstrate the existence of a novel catalytically active AKR, which is associated with mitochondria and expressed mainly in steroid-sensitive tissues.
- Weber, Susanne,Salabei, Joshua K.,M?ller, Gabriele,Kremmer, Elisabeth,Bhatnagar, Aruni,Adamski, Jerzy,Barski, Oleg A.
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p. 6531 - 6545
(2015/03/30)
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- DEHYDROGENATION CATALYST, AND CARBONYL COMPOUND AND HYDROGEN PRODUCTION METHOD USING SAID CATALYST
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Objects of the present invention are to provide a novel dehydrogenation reaction catalyst, to provide a method that can produce a ketone, an aldehyde, and a carboxylic acid with high efficiency from an alcohol, and to provide a method for efficiently producing hydrogen from an alcohol, formic acid, or a formate, and they are accomplished by a catalyst containing an organometallic compound of Formula (1).
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Page/Page column
(2015/03/31)
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- Kinetic solvent isotope effect in steady-state turnover by CYP19A1 suggests involvement of Compound 1 for both hydroxylation and aromatization steps
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CYP19A1, or human aromatase catalyzes the conversion of androgens to estrogens in a three-step reaction through the formation of 19-hydroxy and 19-aldehyde intermediates. While the first two steps of hydroxylation are thought to proceed through a high-valent iron-oxo species, controversy exists surrounding the identity of the reaction intermediate that catalyzes the lyase and aromatization reaction. We investigated the kinetic isotope effect on the steady-state turnover of Nanodisc-incorporated human CYP19A1 to explore the mechanisms of this reaction. Our experiments reveal a significant (～2.5) kinetic solvent isotope effect for the C10-C19 lyase reaction, similar to that of the first two hydroxylation steps (2.7 and 1.2). These data implicate the involvement of Compound 1 as a reactive intermediate in the final aromatization step of CYP19A1.
- Khatri, Yogan,Luthra, Abhinav,Duggal, Ruchia,Sligar, Stephen G.
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p. 3117 - 3122
(2014/11/08)
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- Catalytic asymmetric torgov cyclization: A concise total synthesis of (+)-estrone
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An asymmetric Torgov cyclization, catalyzed by a novel, highly Bronsted acidic dinitro-substituted disulfonimide, is described. The reaction delivers the Torgov diene and various analogues with excellent yields and enantioselectivity. This method was applied in a very short synthesis of (+)-estrone.
- Prevost, Sebastien,Dupre, Nathalie,Leutzsch, Markus,Wang, Qinggang,Wakchaure, Vijay,List, Benjamin
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supporting information
p. 8770 - 8773
(2014/08/18)
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- NONSTEROIDAL AND STEROIDAL COMPOUNDS WITH POTENT ANDROGEN RECEPTOR DOWN-REGULATION AND ANTI PROSTATE CANCER ACTIVITY
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Nonsteroid and steroid compounds that cause down-regulation of the androgen receptor (AR), both full length and splice variant, induce apoptosis and inhibit proliferation of inhibiting proliferation and migration of androgen sensitive cancer cells. The steroid compounds and nonsteroid compounds may be agents for the prevention and/or treatment of cancer, including prostate cancer, castration resistant prostate cancer, bladder cancer, pancreatic cancer, hepatocellular carcinoma, benign prostatic hyperplasia (BPH), Kennedy's disease, androgenetic alopecia, breast cancer, androgen-insensitive syndrome, and spinal and bulbar muscular atrophy.
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Page/Page column 51
(2014/10/18)
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- Cooperative catalysis by iridium complexes with a bipyridonate ligand: Versatile dehydrogenative oxidation of alcohols and reversible dehydrogenation-hydrogenation between 2-propanol and acetone
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Going into reverse: An efficient and versatile catalytic system for the dehydrogenative oxidation of alcohols under extremely mild conditions has been developed using a Cp*Ir complex with bipyridonate ligand as catalyst (see scheme, Cp=pentamethylcyclopentadienyl). Reversible and repetitive transformation between 2-propanol and acetone by catalytic dehydrogenation- hydrogenation is also achieved. Copyright
- Kawahara, Ryoko,Fujita, Ken-Ichi,Yamaguchi, Ryohei
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supporting information
p. 12790 - 12794
(2013/02/22)
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- Conversion of human steroid 5β-reductase (AKR1D1) into 3β-hydroxysteroid dehydrogenase by single point mutation E120H: Example of perfect enzyme engineering
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Human aldo-keto reductase 1D1 (AKR1D1) and AKR1C enzymes are essential for bile acid biosynthesis and steroid hormone metabolism. AKR1D1 catalyzes the 5β-reduction of Δ4-3- ketosteroids, whereas AKR1C enzymes are hydroxysteroid dehydrogenases (HSDs). These enzymes share high sequence identity and catalyze 4-pro-(R)-hydride transfer from NADPH to an electrophilic carbon but differ in that one residue in the conserved AKR catalytic tetrad, His120 (AKR1D1 numbering), is substituted by a glutamate in AKR1D1. We find that the AKR1D1 E120H mutant abolishes 5β-reductase activity and introduces HSD activity. However, the E120H mutant unexpectedly favors dihydrosteroids with the 5α-configuration and, unlike most of the AKR1C enzymes, shows a dominant stereochemical preference to act as a 3β-HSD as opposed to a 3α-HSD. The catalytic efficiency achieved for 3β-HSD activity is higher than that observed for any AKR to date. High resolution crystal structures of the E120H mutant in complex with epiandrosterone, 5β-dihydrotestosterone, and Δ4-androstene-3,17-dione elucidated the structural basis for this functional change. The glutamate-histidine substitution prevents a 3-ketosteroid from penetrating the active site so that hydride transfer is directed toward the C3 carbonyl group rather than the Δ4-double bond and confers 3β-HSD activity on the 5β-reductase. Structures indicate that stereospecificity of HSD activity is achieved because the steroid flips over to present its α-face to the A-face of NADPH. This is in contrast to the AKR1C enzymes, which can invert stereochemistry when the steroid swings across the binding pocket. These studies show how a single point mutation in AKR1D1 can introduce HSD activity with unexpected configurational and stereochemical preference.
- Chen, Mo,Drury, Jason E.,Christianson, David W.,Penning, Trevor M.
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experimental part
p. 16609 - 16622
(2012/07/30)
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- Oxidation of dihydrotestosterone by human cytochromes P450 19A1 and 3A4
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Dihydrotestosterone is a more potent androgen than testosterone and plays an important role in endocrine function. We demonstrated that, like testosterone, dihydrotestosterone can be oxidized by human cytochrome P450 (P450) 19A1, the steroid aromatase. The products identified include the 19-hydroxy-and 19-oxo derivatives and the resulting Δ1,10-, Δ5,10-, and Δ9,10-dehydro 19-norsteroid products (loss of 19-methyl group). The overall catalytic efficiency of oxidation was ～10-fold higher than reported for 3α-reduction by 3α-hydroxysteroid dehydrogenase, the major enzyme known to deactivate dihydrotestosterone. These and other studies demonstrate the flexibility of P450 19A1 in removing the 1- and 2-hydrogens from 19-norsteroids, the 2-hydrogen from estrone, and (in this case) the 1-, 5β-, and 9β-hydrogens of dihydrotestosterone. Incubation of dihydrotestosterone with human liver microsomes and NADPH yielded the 18- and 19-hydroxy products plus the Δ1,10-dehydro 19-nor product identified in the P450 19A1 reaction. The 18- and 19-hydroxylation reactions were attributed to P450 3A4, and 18- and 19-hydroxydihydrotestosterone were identified in human plasma and urine samples. The change in the pucker of the A ring caused by reduction of the Δ4,5 bond is remarkable in shifting the course of hydroxylation from the 6β-, 2β-, 1β-, and 15β-methylene carbons (testosterone) to the axial methyl groups (18, 19) in dihydrotestosterone and demonstrates the sensitivity of P450 3A4, even with its large active site, to small changes in substrate structure.
- Cheng, Qian,Sohl, Christal D.,Yoshimoto, Francis K.,Guengerich, F. Peter
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p. 29554 - 29567,14
(2012/12/12)
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- Oxidation of dihydrotestosterone by human cytochromes P450 19A1 and 3A4
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Dihydrotestosterone is a more potent androgen than testosterone and plays an important role in endocrine function. We demonstrated that, like testosterone, dihydrotestosterone can be oxidized by human cytochrome P450 (P450) 19A1, the steroid aromatase. The products identified include the 19-hydroxy-and 19-oxo derivatives and the resulting Δ1,10-, Δ5,10-, and Δ9,10-dehydro 19-norsteroid products (loss of 19-methyl group). The overall catalytic efficiency of oxidation was ～10-fold higher than reported for 3α-reduction by 3α-hydroxysteroid dehydrogenase, the major enzyme known to deactivate dihydrotestosterone. These and other studies demonstrate the flexibility of P450 19A1 in removing the 1- and 2-hydrogens from 19-norsteroids, the 2-hydrogen from estrone, and (in this case) the 1-, 5β-, and 9β-hydrogens of dihydrotestosterone. Incubation of dihydrotestosterone with human liver microsomes and NADPH yielded the 18- and 19-hydroxy products plus the Δ1,10-dehydro 19-nor product identified in the P450 19A1 reaction. The 18- and 19-hydroxylation reactions were attributed to P450 3A4, and 18- and 19-hydroxydihydrotestosterone were identified in human plasma and urine samples. The change in the pucker of the A ring caused by reduction of the Δ4,5 bond is remarkable in shifting the course of hydroxylation from the 6β-, 2β-, 1β-, and 15β-methylene carbons (testosterone) to the axial methyl groups (18, 19) in dihydrotestosterone and demonstrates the sensitivity of P450 3A4, even with its large active site, to small changes in substrate structure.
- Cheng, Qian,Sohl, Christal D.,Yoshimoto, Francis K.,Guengerich, F. Peter
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p. 29554 - 29567
(2013/01/14)
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- Protecting group effect on the 1,2-dehydrogenation of 19-hydroxysteroids: a highly efficient protocol for the synthesis of estrogens
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19-O-Acylation was found to be indispensable for 1,2-dehydrogenation of 19-hydroxyandrost-4-ene-3,17-dione 1a with DDQ as an oxidant after exploring a variety of C-19 substituents. 1,2-Dehydrogenation in combination with subsequent A-ring aromatization via retro-aldol reaction provided a flexible and efficient protocol for the synthesis of estrogens. To demonstrate the utility of the protocol, pharmaceutically attractive estrogens were synthesized from easily available 19-hydroxy-4-ene-3-keto steroids.
- Jing, Yu,Xu, Cheng-Gong,Ding, Kai,Lin, Jing-Rong,Jin, Rong-Hua,Tian, Wei-Sheng
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scheme or table
p. 3242 - 3245
(2010/08/19)
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- 4- and 6-(p-Sulphamoylphenyl)androstenediones: Studies of aromatase inhibitor-based oestrone sulphatase inhibition
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4-(p-Sulphamoylphenyl)androstenedione (3) and 6α-p-sulphamoylphenyl analogues 12-14 were synthesised and tested as aromatase inhibitors as well as oestrone sulphatase inhibitors in human placental microsomes. All of the p-sulphamoylphenyl compounds synthesised were powerful inhibitors of aromatase with apparent Ki values ranging between 30 and 97 nM. In addition, the aromatase inhibitory activities of 6α-p-hydroxyphenyl compounds 9-11, which may be produced from their respective sulphamoylphenyl compounds by action of oestrone sulphatase, were also high in a range of 23 and 75 nM of the K i values. On the other hand, all of the sulphamoylphenyl compounds were poor inhibitors of oestrone sulphatase with more than about 200 μM of IC25 values. Although the present findings of the oestrone sulphatase inhibition are disappointing, such attempts may be valuable to develop a new class of drugs having a dual function, aromatase inhibitor and oestrone sulphatase inhibitor, for the treatment of oestrogen-dependent breast cancer.
- Watari, Yoko,Yamaguchi, Satoshi,Takahashi, Madoka,Nagaoka, Masao,Numazawa, Mitsuteru
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experimental part
p. 891 - 896
(2010/10/03)
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- Rapid and selective catalytic oxidation of secondary alcohols at room temperature by using (N-Heterocyclic Carbene)-Ni0 systems
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The selective, anaerobic catalytic oxidation of secondary alcohols at room temperature by using an in situ (N-heterocyclic carbene)-Ni0 system is presented. The use of non-anhydrous, non-degassed 2,4-dichlorotoluene as both the oxidant and the solvent allows for very short reaction times and very high yields. In addition, a well-defined (N-heterocyclic carbene)-Ni0 complex was synthesized and applied to these oxidation reactions.
- Berini, Christophe,Winkelmann, Ole H.,Otten, Jennifer,Vicic, David A.,Navarro, Oscar
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supporting information; experimental part
p. 6857 - 6860
(2010/08/03)
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- A novel, versatile D→BCD steroid construction strategy, iIIustrated by the enantioselective total synthesis of estrone
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Chemical Equation presented A general steroid synthesis Is presented that relies on prior formation of three stereogenlc centers (C8, C13, and C14) on a D ring template, followed by C- and B-ring cyclizatlons. The assembly of the key D ring template, achieved by a 3-component conjugate addition/alkylation process, allows Introduction of structural variety as required. The method Is illustrated by the total synthesis of estrone via a C-ring closing metathesis and a B-ring Heck cyclization.
- Foucher, Vincent,Gulzzardi, Benedetta,Groen, Marinus B.,Light, Mark,Linclau, Bruno
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supporting information; experimental part
p. 680 - 683
(2010/04/02)
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- Enantioselective synthesis of (+)-estrone exploiting a hydrogen bond-promoted Diels?Alder reaction
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Starting from Danes diene and methylcyclopentenedione, (+)-estrone is synthesized along the Quinkert?Dane route in 24% total yield. The key step is an enantioselective Diels?Alder reaction promoted by an amidinium catalyst as efficiently as by a traditional Ti-TADDOLate Lewis acid.
- Weimar, Marko,Duerner, Gerd,Bats, Jan W.,Goebel, Michael W.
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supporting information; experimental part
p. 2718 - 2721
(2010/07/17)
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- Microwave-assisted demethylation of methyl aryl ethers using an ionic liquid
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An efficient demethylation of methyl aryl ethers using an ionic liquid, 1-n-butyl-3-methylimidazolium bromide ([bmim][Br]) has been developed. Methyl aryl ethers are successfully cleaved by the halide anion of [bmim][Br], without aid of any other activating agents. In this reaction, microwave irradiation was found to be crucial for the effective conversion. The newly developed protocol is a very attractive green chemical process as it utilizes minimal amount of cleaving reagents and does not require additional activating agents or solvents. Under the conditions described herein, a broad range of methyl aryl ethers were converted to the corresponding phenolic compounds in moderate to excellent yields in a short time. Georg Thieme Verlag Stuttgart New York.
- Park, Jiyeon,Chae, Junghyun
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experimental part
p. 1651 - 1656
(2010/08/22)
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- Chemical aromatization of 19-hydroxyandrosta-1,4-diene-3,17-dione with acid or alkaline: Elimination of the 19-hydroxymethyl group as formaldehyde
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In order to determine whether or not a 19-hydroxymethyl group of 19-hydroxyandrosta-1,4-diene-3,17-dione (2, 19-hydroxy ADD), an intermediate of aromatase-catalyzed estrone formation from ADD, a suicide substrate of aromatase, is eliminated as formaldehyde, we examine chemical nature of removal of the 19-hydroxymethyl group. 19-Acetate 3 and 19-tert-butyldimethylsiloxy compound 4 are known to convert rapidly to estrone with treatment of NaOH or n-Bu4NF. Since compound 2 was unstable and unobtainable under these conditions, compounds 3 and 4 as equivalents to compound 2 were used in this study. The acetate 3 with 5 mol/l HCl in acetone and 10% KOH in MeOH along with the silyl ether 4 with 5 mol/l HCl in acetone and 1 mol/l n-Bu4NF in THF gave formaldehyde and estrone in which a ratio of the aldehyde to estrone was near 1. This result indicates that the 19-hydroxymethyl groups of compound 3 and 4 are eliminated as formaldehyde along with estrone derived from the steroid skeleton under the acid or base treatment. The findings suggest that a single hydroxylation at the 19 carbon of ADD (1) would be, chemically, all that was required for estrone formation.
- Numazawa, Mitsuteru,Yamashita, Kouwa,Kimura, Nao,Takahashi, Madoka
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experimental part
p. 208 - 211
(2009/04/14)
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- PROCESS FOR AROMATIZING 19-NORANDROST-4-EN-3-ONES TO ESTRA-1,3,5(10)-TRIENES
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The present invention relates to a process for aromatizing 19-norandrost-4-en-3-ones (formula (II)) to astra-1,3,5(10)-trienes (formula (I))
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Page/Page column 8-9
(2009/07/03)
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- Heterogeneous palladium multi-task catalyst for sequential Heck-reduction-cyclization (HRC) reactions: influence of the support
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An evaluation study of various palladium supports led to the selection of charcoal as the most efficient system for the preparation of oxindoles by sequential Heck-reduction-cyclization (HRC) reactions. The in situ prepared Pd0/C was not recyclable for further cross-coupling reactions but remains still highly active for reduction processes. The sustainable chemistry described herein allows extremely simple experimental protocol under mild conditions, free of any base, ligand and additive.
- Ibarguren, Oier,Zakri, Cécile,Fouquet, Eric,Felpin, Fran?ois-Xavier
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supporting information; experimental part
p. 5071 - 5074
(2009/12/01)
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- Preparation of 2-Quinolones by sequential heck reduction-cyclization (HRC) reactions by using a multitask palladium catalyst
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One-pot sequential Heck reduction-cyclization (HRC) reactions leading to the synthesis of substituted 2-quinolones have been developed by using a heterogeneous or mixed homogeneous/heterogeneous multitask palladium catalyst with charcoal as a support. The whole sequence occurs under very mild conditions without the need for additives (ligand or base) by taking advantage of the high reactivity of aryldiazonium salts as "super electrophiles". Recycling experiments showed that the reused heterogeneous Pd°/C catalyst was not able to promote another HRC sequence but was, however, still highly active for hydrogenation, hydrodehalogenation, as well as hydrogenolysis reactions.
- Felpin, Francois-Xavier,Coste, Jerome,Zakri, Cecile,Fouquet, Eric
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experimental part
p. 7238 - 7245
(2010/03/25)
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- Harnessing functional plasticity of enzymes: A fluorogenic probe for imaging 17β-HSD10 dehydrogenase, an enzyme involved in Alzheimer's and Parkinson's diseases
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In this paper, we describe the development of a fluorogenic substrate for 17β-hydroxysteroid-dehydrogenase type 10 (17β-HSD10), which is a multifunctional metabolic enzyme fulfilling several metabolic roles (β-oxidation of fatty acids, catabolism of isoleucine, and metabolism of steroids). In recent years, it has emerged as an important stress and pathological marker in neurons and glial cells (expression down-regulation in Parkinson's disease, up-regulation and association with β-amyloid peptide in Alzheimer's disease). Through the iterative molecular design and chemical synthesis described herein, compound 1 was developed, which possesses all required properties for a selective optical reporter substrate: alcohol-ketone optical switching, the ability to function as a good enzyme substrate (expressed in kinetic parameters), cell permeability, and cell retention. Probe 1 provides a blue-to-green/yellow bright switch and enables non-invasive, real-time imaging of 17β-HSD10 in live human cells. The selectivity of reporter 1 was established by the quantitative correlation of metabolic activity to protein expression in human kidney cell line HEK-293T.
- Froemming, Mary K.,Sames, Dalibor
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p. 14518 - 14522
(2008/09/17)
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- A NEW PROCESS FOR THE PREPARATION OF PHENOLIC HYDROXY-SUBSTITUTED COMPOUNDS
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The invention relates to a process for the preparation of a phenolic hydroxy-substituted compound of the general formula (I) by desalkylation of an alkyl aryl ether of the general formula (II) by treatment with a thiourea/aluminium chloride reagent pair, in said general formulae R1 stands for straight chain or branched C1-6 alkyl group; R2, R3, R4, R5 , and R6 have the same or different meanings and stand for hydrogen or halogen atom, hydroxy, carboxy, nitro, oxo, C1-6 alkylcarbonyl, straight chain or branched alkyl or - alkoxy, or aryl group, or R2 and R3 together stand for a 5-7 membered ring or fused ring system; said 5-7 membered ring may be a partially saturated ring optionally substituted with an oxo group or can be an unsaturated ring; or said fused ring system may constitute with the first ring a steroid, preferably an estratriene derivative optionally substituted with an oxo or C1-6 alkylcarbonyloxy group in the 17 position -.
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Page/Page column 15-16
(2008/06/13)
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- Synthesis, reactions, conformation analysis, and NMR spectra of 5,10-epoxy-5ξ,10ξ-estrane-3,17-diones
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On epoxidation of estr-5(10)-ene-3,17-dione, the 5β,10β-epoxide is the major product. The mixture of epoxides was converted into 5,10β-dihydroxy-5α-estrane-3,17-dione, 10α- and 10β-hydroxyestr-4-ene-3,17-dione, and estrone. Due to the sensitivity of the products, 1H NMR was the best way to monitor the reaction pathway.
- Budesinsky, Milos,Fajkos, Jan,Guenter, Jaroslav,Kasal, Alexander
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p. 507 - 518
(2007/10/03)
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- Pharmaceutical composition with tumor necrosis factor A and 2-methoxyestrone-3-0-sulphamate for inhibition of estrone sulphatase
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A composition is described. The composition comprises i) a compound comprising a sulphamate group (“a sulphamate compound”); and ii) a biological response modifier.
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