- Hydrogen peroxide induced activation of gene expression in mammalian cells using boronate estrone derivatives
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Keeping the boron out of the ER: A genetic switch was engineered that activates gene expression in the presence of H2O2 (see scheme). The use of a boronate group on an estrone molecule allows for activation of gene expression through binding of the estrogen receptor only when the boron group is oxidized by H2O2. This sensor is highly sensitive and specific for H2O2. Copyright
- Govan, Jeane M.,McIver, Andrew L.,Riggsbee, Chad,Deiters, Alexander
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- Steroidal lactones as inhibitors of 17β-hydroxysteroid dehydrogenase type 5: Chemical synthesis, enzyme inhibitory activity, and assessment of estrogenic and androgenic activities
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Androgens are well known to play a predominant role in prostate cancer and other androgen-dependent diseases. To decrease the level of androgen testosterone in the prostate, we are interested in developing inhibitors of 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5). This enzyme expressed in the prostate is one of the two enzymes able to convert 4-androstene-3,17-dione into testosterone. From a screening study, it was found that a series of steroid derivatives bearing a lactone on D-ring demonstrated potent inhibition of 17β-HSD5 over-expressed in HEK-293 cells. The results of enzymatic assays using intact cells indicated that a C18-steroid (estradiol or 3-deoxyestradiol) backbone and a spiro-δ-lactone (six-member ring) are important for a strong inhibitory activity. Moreover, the presence of a dimethyl group at the alpha-position of the lactone carbonyl increases the selectivity of the inhibitor toward 17β-HSD5. Compound 26, a 3-deoxyestradiol derivative with a dimethylated spiro-δ-lactone at position 17, possesses the most potent inhibitory activity for 17β-HSD5 (IC50 = 2.9 nM). It showed no binding affinity for estrogen, androgen, progestin and glucocorticoid receptors (ER, AR, PR and GR). A weak proliferative effect was, however, observed on ZR-75-1 (ER+) cells in culture at high concentration (1 μM), but not at 0.03 μM. Interestingly, no significant proliferative effect was detected on Shionogi (AR+) cells in culture in the presence of 0.1 and 1 μM of lactone 26.
- Bydal, Patrick,Luu-The, Van,Labrie, Fernand,Poirier, Donald
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- Nickel-Catalyzed Hydrodeoxygenation of Aryl Sulfamates with Alcohols as Mild Reducing Agents
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The nickel-catalyzed hydrodeoxygenation of aryl sulfamates has been developed with alcohols as mild reductants. A variety of functional groups and heterocycles were tolerated in this reaction system to give the desired products in high yields. In addition, the gram-scale process and stepwise cine-substitution were also achieved with high efficiency.
- Matsuo, Kasumi,Kuriyama, Masami,Yamamoto, Kosuke,Demizu, Yosuke,Nishida, Koyo,Onomura, Osamu
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p. 4449 - 4460
(2021/08/25)
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- Catalytic Reductions Without External Hydrogen Gas: Broad Scope Hydrogenations with Tetrahydroxydiboron and a Tertiary Amine
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Facile reduction of aryl halides with a combination of 5% Pd/C, B2(OH)4, and 4-methylmorpholine is reported. Aryl bromides, iodides, and chlorides were efficiently reduced. Aryl dihalides containing two different halogen atoms underwent selective reduction: I over Br and Cl, and Br over Cl. Beyond these, aryl triflates were efficiently reduced. This combination was broadly general, effectuating reductions of benzylic halides and ethers, alkenes, alkynes, aldehydes, and azides, as well as for N-Cbz deprotection. A cyano group was unaffected, but a nitro group and a ketone underwent reduction to a low extent. When B2(OD)4 was used for aryl halide reduction, a significant amount of deuteriation occurred. However, H atom incorporation competed and increased in slower reactions. 4-Methylmorpholine was identified as a possible source of H atoms in this, but a combination of only 4-methylmorpholine and Pd/C did not result in reduction. Hydrogen gas has been observed to form with this reagent combination. Experiments aimed at understanding the chemistry led to the proposal of a plausible mechanism and to the identification of N,N-bis(methyl-d3)pyridin-4-amine (DMAP-d6) and B2(OD)4 as an effective combination for full aromatic deuteriation. (Figure presented.).
- Korvinson, Kirill A.,Akula, Hari K.,Malinchak, Casina T.,Sebastian, Dellamol,Wei, Wei,Khandaker, Tashrique A.,Andrzejewska, Magdalena R.,Zajc, Barbara,Lakshman, Mahesh K.
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supporting information
p. 166 - 176
(2020/01/02)
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- Development of a gram-scale synthesis of pbrm, an irreversible inhibitor of 17beta-hydroxysteroid dehydrogenase type 1
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Efforts toward the development of a reliable gram scale synthesis of PBRM, a potent and selective steroidal covalent inhibitor of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), are described. Among the three synthetic routes (C-E) developed herein, route E is the most efficient one with only 6 chemical steps from commercially available estrone, and an overall yield of 13% leading to PBRM with a high HPLC grade purity (99.7%) after recrystallization. Important improvements have been achieved in this sequence from previous reported routes (A and B). Notably, we used a palladium catalyzed Suzuki-Miyaura cross-coupling reaction to rapidly install the requested C3 chain on estrone. Also, catalytic hydrogenation of the C16-enone was shortened by half using Pearlman's catalyst. Finally, we used a selective bromination through deoxygenation of alcohol at the last step of the sequence to provide PBRM without dehydration of its carboxamide functionality, a persistent problem observed in other routes. Crystals of PBRM were also obtained from recrystallization in acetonitrile and submitted to x-ray analysis, which confirmed the PBRM structure. This work now makes it possible to start a proof-of-principle in a non-human primate model for the treatment of endometriosis, while supporting its future pharmacological development.
- Maltais, René,Poirier, Donald
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p. 2323 - 2335
(2019/10/14)
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- Efficient and selective hydrogenation of C-O bonds with a simple sodium formate catalyzed by nickel
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A Ni-catalyzed hydrogenation of C-O compounds with sodium formate is developed. Various esters, i.e. aryl, alkenyl, benzyl pivalates, and even the aryl ethers, were efficiently reduced with a loading of nickel catalysts down to 0.5 mol%. Reactive functional groups such as C-C double bonds, carbonyl, CN, MeS and halogen groups are tolerable. This reaction can be used for the modification of complex molecules and carried out at a large scale.
- Xi, Xiaoxiang,Chen, Tieqiao,Zhang, Ji-Shu,Han, Li-Biao
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supporting information
p. 1521 - 1524
(2018/02/19)
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- Selective Reductive Removal of Ester and Amide Groups from Arenes and Heteroarenes through Nickel-Catalyzed C?O and C?N Bond Activation
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An inexpensive nickel(II) catalyst and a hydrosilane were used for the efficient reductive defunctionalization of aryl and heteroaryl esters through a decarbonylative pathway. This versatile method could be used for the removal of ester and amide functional groups from various organic molecules. Moreover, a scale-up experiment and a synthetic application based on the use of a removable carboxylic acid directing group highlight the usefulness of this reaction.
- Yue, Huifeng,Guo, Lin,Lee, Shao-Chi,Liu, Xiangqian,Rueping, Magnus
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supporting information
p. 3972 - 3976
(2017/03/27)
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- Nickel-catalyzed reductive defunctionalization of esters and amides to aromatic hydrocarbons
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The removal of ester and amide groups is of fundamental significance in organic syntheses. Under non-catalytic conditions, hydride sources are chiefly used for their reduction. Recently developed Ni-catalyzed one-pot reductive activation of esters and ami
- Mondal, Manoj,Bharali, Pankaj
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p. 13211 - 13214
(2017/11/27)
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- A facile and mild Pd-catalyzed one-pot process for direct hydrodeoxygenation (HDO) phenols to arenes through a ArOSO2F intermediates transformation
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A practical one-pot process for hydrodeoxygenation (HDO) of phenolic derivatives to their corresponding arenes was developed. This method provided a facile route to upgrading bio-oil. The substrate scope of this protocol was wide, complicated and multi-phenolic compounds were also smoothly hydrodeoxygenated to their corresponding arenes.
- Wang, Xiao-Yan,Leng, Jing,Wang, Shi-Meng,Asiri, Abdullah M.,Marwani, Hadi M.,Qin, Hua-Li
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supporting information
p. 2340 - 2343
(2017/05/29)
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- Deoxidizing reduction method for phenolic compound
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The invention discloses a deoxidizing reduction method for a phenolic compound. The method comprises the following steps: reacting the phenolic compound with sulfuryl fluoride, thereby generating aryl fluorosulfonate; adding palladium acetate as a catalyst, 1,3-diphenylphosphine propane ligand and NH3/HCOOH as transferring hydrogen reducing agent; acquiring the corresponding arene after completing the reaction. On the basis of the molar weight of the raw material phenol, the dosage of the palladium acetate catalyst is 2mol%-5mol%; the dosage of the 1,3-diphenylphosphine propane ligand is 1.2 times of the dosage of the palladium acetate catalyst; the removal of monomolecular hydroxy requires 4 times of equivalent transferring hydrogen reducing agent. Most reagents used according to the invention are low-cost and are easily acquired. The dosage of the high-cost palladium acetate catalyst is less and the low-toxicity dimethyl sulfoxide is used as the solvent, so that the method is green and economical. Besides, the reaction time according to the invention is short and the whole process requires no heating and can be completed under room temperature, so that the method has the characteristics of high speed, energy-saving effect, and the like.
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Paragraph 0038; 0039; 0040
(2017/11/04)
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- A Fluorinated Ligand Enables Room-Temperature and Regioselective Pd-Catalyzed Fluorination of Aryl Triflates and Bromides
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A new biaryl monophosphine ligand (AlPhos, L1) allows for the room-temperature Pd-catalyzed fluorination of a variety of activated (hetero)aryl triflates. Furthermore, aryl triflates and bromides that are prone to give mixtures of regioisomeric aryl fluorides with Pd-catalysis can now be converted to the desired aryl fluorides with high regioselectivity. Analysis of the solid-state structures of several Pd(II) complexes, as well as density functional theory (DFT) calculations, shed light on the origin of the enhanced reactivity observed with L1.
- Sather, Aaron C.,Lee, Hong Geun,De La Rosa, Valentina Y.,Yang, Yang,Müller, Peter,Buchwald, Stephen L.
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supporting information
p. 13433 - 13438
(2015/11/09)
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- Nickel-catalyzed one-pot deoxygenation and reductive homocoupling of phenols via C-O activation using TCT reagent
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A new method for C-O bond activation of phenolic compounds has been achieved using 2,4,6-trichloro-1,3,5-triazine to utilize in one-pot Ni-catalyzed deoxygenation and reductive homocoupling reactions. With this simple method, phenolic compounds were converted to their corresponding arenes or biaryl compounds under mild conditions. The introduced methodology has a broad scope and demonstrates good functional group compatibility.
- Iranpoor, Nasser,Panahi, Farhad
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supporting information
p. 214 - 217
(2015/01/30)
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- STEROID-DERIVED CYCLOPAMINE ANALOGS AND METHODS FOR USING THE SAME IN THE PREVENTION OR TREATMENT OF CANCER
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The present invention relates to steroid-derived cyclopamine analogs and methods for using the same for inhibiting sonic hedgehog signaling and preventing or treating cancer. A method for synthesizing the analogs of the present invention from a steroid is also provided.
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Page/Page column 29
(2009/06/27)
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- Inhibitors of type 5 and type 3 17β-hydroxysteroid dehydrogenase and methods for their use
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Novel methods of medical treatment and/or inhibition of development of diseases are disclosed for diseases that are sensitive to androgenic or estrogenic activity. The treatments utilize inhibitors of type 5 and/or type 3 17β-hydroxysteroid dehydrogenase. Novel inhibitors of type 5 17β-hydroxysteroid dehydrogenase are also disclosed, as are novel inhibitors of type 3 17β-hydroxysteroid dehydrogenase.
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- Synthesis of and Chemical Model Reaction Studies with 3-Deoxyandrogens: Evidence Supporting a 2,3-Enolization Hypothesis in Human Placental Aromatase Catalysis
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A number od hitherto undescribed Δ2- and Δ3-3-deoxy-5α-androgen derivatives (17β,19-diols 12 and 13, 19-hydroxy-17-ketones 16 and 17, 19-oxo-17-ketones 18 and 19) were synthesized in good yield.The lithium-ammonia reduction of 19-(te
- Oh, Soonsin S.,Robinson, Cecil H.
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p. 2237 - 2244
(2007/10/02)
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- Metal-assisted reactions. Part 20. Catalytic transfer hydrogenolysis of phenolic C-O bonds
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After conversion of phenols into O-pseudosaccharyl ethers (2) catalytic transfer hydrogenolysis with Pd/C catalyst and sodium phosphinate as hydrogen donor gave arenes (ArH) in good yield. As an example of the application of this reaction in synthesis, oestrone was onverted into oestratrienone in a high yielding, one step reaction.
- Brigas,Johnstone
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p. 5789 - 5790
(2007/10/02)
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- PALLADIUM-CATALYZED TRIETHYLAMMONIUM FORMATE REDUCTION OF ARYL TRIFLATES. A SELECTIVE METHOD FOR THE DEOXYGENATION OF PHENOLS
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Phenols can be selectively deoxygenated by reduction of the corresponding aryl triflates with triethylammonium formate in the presence of a homogeneous palladium catalyst.
- Cacchi, Sandro,Ciattini, Pier Giuseppe,Morera, Enrico,Ortar, Giorgio
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p. 5541 - 5544
(2007/10/02)
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