- Nickel-Catalyzed Intramolecular Decarbonylative Coupling of Aryl Selenol Esters
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This report describes a method for Ni-catalyzed intramolecular decarbonylative coupling, which enables the conversion of areneselenol esters to diaryl selenides. The inexpensive and readily available catalyst can be employed under mild reaction conditions for the construction of structurally diverse diaryl selenides, including heterocyclic and natural product derivatives. (Figure presented.).
- Bai, Jin-Hua,Qi, Xiu-Juan,Sun, Wei,Yu, Tian-Yang,Xu, Peng-Fei
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supporting information
p. 2084 - 2088
(2021/03/01)
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- METHODS OF ACTIVATING MICROGLIAL CELLS
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The present disclosure provides methods of using compositions that inhibit SH2-containing inositol 5'-phosphatases (SHIPs) for activating microglial cells, as well as methods for using such compositions for treatment or ameliorating of neurodegenerative disorders in a subject.
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Page/Page column 50; 52
(2020/02/23)
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- HUMAN GHRELIN O-ACYL TRANSFERASE INHIBITORS
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A class of cyanosteroid compounds that efficiently inhibit ghrelin acylation by ghrelin O-acyltransferase. The compounds have a steroid scaffold with α,β-unsaturated ketone in the A ring position such an a-cyanoenone. Exemplary compounds include (5S,8S,9S,10S, 13S,14S)-10,13-dimethyl-3-oxo-4,5,6,7,8,9,10,11,12,13,14,15,16,17- tetradecahydro-3H-cyclopenta[a]phenanthrene-2-carbonitrile.
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- AMPHIPHILIC COMPOUNDS WITH NEUROPROTECTIVE PROPERTIES
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The present invention provides amphiphilic compounds with tetradecahydrophenanthrene skeleton and their enantiomers, exhibiting neuroprotective effects, their use as medicaments for treating neuropsychiatric disorders associated with an imbalance in glutamatergic neurotransmitter system, such as ischemic damage of CNS, neurodegenerative changes and disorders of CNS, affective disorders, depression, post-traumatic stress disorder and diseases related to stress, anxiety, schizophrenia and psychotic disorders, pain, addiction, multiple sclerosis, epilepsy, glioma, and a pharmaceutical composition containing said compound.
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Page/Page column 36
(2016/03/22)
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- SHIP INHIBITION TO COMBAT OBESITY
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The present invention relates to the use of SHIP1 inhibitors and pan-SHIP1/2 inhibitors in various methods, including, without limitation: (i) a method to treat obesity or reduce body fat of an obese subject; (ii) a method to limit bone development in a subject suffering from an osteopetrotic or sclerotic disease; (iii) a method to treat or prevent diabetes; (iv) a method to reduce glucose intolerance or insulin resistance; and (v) a method to lower cholesterol.
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Paragraph 00194
(2015/01/16)
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- A New Class of Potent N-Methyl- d -Aspartate Receptor Inhibitors: Sulfated Neuroactive Steroids with Lipophilic D-Ring Modifications
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N-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that play a crucial role in excitatory synaptic transmission. However, the overactivation of NMDARs can lead to excitotoxic cell damage/death, and as such, they play a role in numerous neuropathological conditions. The activity of NMDARs is known to be influenced by a wide variety of allosteric modulators, including neurosteroids, which in turn makes them promising therapeutic targets. In this study, we describe a new class of neurosteroid analogues which possess structural modifications in the steroid D-ring region. These analogues were tested on recombinant GluN1/GluN2B receptors to evaluate the structure-activity relationship. Our results demonstrate that there is a strong correlation between this new structural feature and the in vitro activity, as all tested compounds were evaluated as more potent inhibitors of NMDA-induced currents (IC50 values varying from 90 nM to 5.4 μM) than the known endogeneous neurosteroid-pregnanolone sulfate (IC50 = 24.6 μM).
- Kudova, Eva,Chodounska, Hana,Slavikova, Barbora,Budesinsky, Milos,Nekardova, Michaela,Vyklicky, Vojtech,Krausova, Barbora,Svehla, Pavel,Vyklicky, Ladislav
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p. 5950 - 5966
(2015/08/24)
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- SHIP INHIBITORS AND USES THEREOF
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The present invention relates to SHIP inhibitor compounds and methods for using these compounds. In particular, the present invention discloses the following methods: (i) a method of treating graft versus host disease in a subject; (ii) a method of inhibiting a SHIP1 protein in a cell; (iii) a method of selectively inhibiting a SHIP1 protein in a cell; (iv) a method for treating or preventing graft-versus-host disease (GVHD) in a recipient of an organ or tissue transplant; (v) a method of modulating SHIP activity in a cell expressing SHIP1 or SHIP2; (vi) a method of ex vivo or in vitro treatment of transplants; (vii) a method of inhibiting tumor growth and metastasis in a subject; (viii) a method of treating a hematologic malignancy in a subject; (ix) a method of inducing apoptosis of multiple myeloma cells; (x) a method of treating multiple myeloma in a subject; (xi) a method of inhibiting the proliferation of a human breast cancer cell; and (xii) a method of treating breast cancer in a subject.
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Page/Page column 31-33
(2011/10/31)
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- Androstanes with modified carbon skeletons
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Four sterane hydrocarbons were prepared for comparisonwith fossil organic biomarkers in geological samples from Oman. 17ss-Methylestrane was prepared in six steps (36% overall yield) from estrone methyl ether. Key steps of this sequence were a Wittig olefination and Birch reduction of the A-ring. 17ss-Methylandrostane was obtained in four steps (85% overall yield) from trans-androsterone by four functional group interconverting reactions, including aWittig olefination. 17ss-Methyl-and 2α-methyl-A-nor-5α- androstanes (14 and 15% overall yields, respectively) were also prepared from trans-androsterone. Key steps were the thallium trinitrate mediated ring contractions of A-ring ketones to A-nor-2-carboxylic acids. Defunctionalization in the four syntheses was achieved by catalytic hydrogenation, Huang-Minlon reduction, Barton decarboxylation, and Bu3SnH-mediated reduction of a chloromethyl group, respectively.
- Norden, Sascha,Bender, Matthias,Rullkoetter, Juergen,Christoffers, Jens
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experimental part
p. 4543 - 4550
(2011/09/16)
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- One-pot reductive cleavage of exo-olefin to methylene with a mild ozonolysis-Clemmensen reduction sequence
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A one-pot exo-olefin reductive cleavage was for the first time developed. The reaction could proceed under a mild condition avoiding the use of hazardous and expensive reagents. Meanwhile, a TMSCl-mediated Clemmensen reduction in alcoholic solvent was also examined.
- Xu, Shu,Toyama, Takayuki,Nakamura, Jun,Arimoto, Hirokazu
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scheme or table
p. 4534 - 4537
(2010/10/02)
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- Novel and efficient synthesis and antifungal evaluation of 2,3-functionalized cholestane and androstane derivatives
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Synthetic modifications of cholesterol and other traditional steroid molecules have become a promising area for the exploration and development of novel antifungal agents, especially with respect to the development of fatty-acid esters of steroids. In addition, 2,3-functionalized steroids are also compounds with potentially interesting biological properties and proper functionalization of 2,3-steroids can lead to the development of efficient syntheses of building blocks for novel fatty-acid esters of steroids. In this Letter, we outline a novel and efficient approach to the synthesis of 2,3-functionalized cholestane and androstane derivatives and present their promising preliminary antifungal activities against a number of fungal species.
- Jursic, Branko S.,Upadhyay, Sunil Kumar,Creech, Clinton C.,Neumann, Donna M.
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supporting information; experimental part
p. 7372 - 7375
(2011/02/23)
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- Homogeneous catalytic hydroaminomethylation of steroids with aminoalcohols
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Rhodium-catalyzed carbonylation of several Δ16 steroids was carried out in the presence of aminoalcohols and new hydroxy-aminomethyl derivatives have been obtained in moderate to good yields. The multi-step reaction is highly chemo- and regioselective. The new compounds containing the hydroxy function can serve as starting materials for further functionalization of the steroid skeleton.
- Nagy, Emese,Heil, Balint,Toroes, Szilard
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p. 101 - 105
(2007/10/03)
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- Factors Affecting the Facial Selectivity in the Hydroboration of Steroidal Δ5-Enes
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A comparison between the facial selectivity observed in the hydroboration of some androst-5-enes and B-norandrost-5-enes does not parallel the differences between the calculated force field energies of α- and β-cyclobutane models suggesting that in this case the facial selectivity is not determined by the four centre transition state but by the ease of formation of the initial ?-complexes between the alkene and the borane.
- Arantes, Simone F.,Hanson, James R.,Liman, Mansur D.,Manickavasagar, Revathy,Uyanik, Cavit
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p. 2381 - 2397
(2007/10/03)
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- Phosphonate and phosphate monoester hydrolysis
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The reaction of phosphonate and phosphate monoesters with an epoxide yields β-hydroxyalkyl derivatives which upon treatment with base quantitatively release the original alcohol moiety of the ester in a relatively rapid simple procedure.
- Sprecher,Oppenheimer,Nov
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p. 115 - 120
(2007/10/02)
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- The Predominance and Quantification of Steric Effects in the Solvolysis of Secondary Aliphatic Esters
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The solvolysis rates of 35 tosylates in hexafluoroisopropyl alcohol are measured and compared to MM2 calculated strain energies, ΔSI, between weighted sp3 states and the lowest sp2 state.For unhindered (pseudo)equatorially substituted cycloalkyl tosylates a linear correlation, free from ambiguities involved, e.g., with the leaving group simulation, is obtained which shows a sensitivity of m=1.04+/-0.05, indicating an extremely late transition state or limiting behavior.Based on the corresponding equation, it is shown that alkyl substituents in the γ- and in the β-position do not promote significant rate increases, even when there is an antiperiplanar disposition between the leaving group and a migrating β-methyl substituent.Instead, these substituents can lead to substantial ΔG* increase (by up to 5 kcal/mol in comparison to the ΔSI prediction), which is related to steric hindrance of solvation and/or hindrance for elimination. 17-(Tosyloxy)androstanes show extremely large epimeric rate ratios of>30000; these are not due to anchimeric assistance but only to the exceedingly slow reaction of the hindered 17β isomer, whereas the fast reaction of the 17α tosylate (e.g. 200 times higher than cyclopentyl tosylate) is in line with the ΔSI calculation. endo-Bicycloheptane esters show evidence for steric hindrance; exo-norbornyl tosylate has, however, a ΔG* value lower by 4 kcal/mol than predicted. ks/kc values, obtained by rate comparison in 80percent ethanol and 97percent HFIP, vary between 0.5 and 300, mainly as a result of different steric hindrance to rearside nucleophilic subnstitution
- Schneider, Hans-Joerg,Becker, Norman,Schmidt, Guenther,Thomas, Fred
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p. 3602 - 3607
(2007/10/02)
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- 1H NMR Analyses, Shielding Mechanisms, Coupling Constants, and Comformations is Steroids Bearing Halogen, Hydroxy, Oxo Groups, and Double Bonds
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The 1H NMR analyses of 16 5αH-androstanes and one progesterone analogue furnish shifts and coupling constants for the basic steroid skeleton and substituent-induced shifts (SIS) for oxo, hydroxy, and halogen groups as well as for a Δ double bond.It is shown how a single 2D experiment complemented by a NOE difference spectrum can lead to complete assignments even with the most complicated spin systems compirising, e.g., 29 strongly coupled protons within only 1 ppm; the accurancy of information from 2D techniques is evaluated by comparison to some 1D and computer-simulated spectra.On the basis of up to six simultaneously observable couplings, a special approach is used to scan the conformational space of particularly flexible parts.Intermediate conformations between half-chair and twist are obtained with a torsional C14-C15-C16-C17 angle of φ ca. 20 deg for the D ring with a sp2 (17-oxo) carbon and of φ ca. 10 deg with only sp3 carbon atoms; the observed flat profiles, however, allow also for mixtures of different conformations, which is supported by MM2 calculations.For the Δ-3-oxo A ring, a sofa conformation is favored compared to a half-chair geometry.The observed shielding effects of heterosubstituents are partially at variance with the few earlier observations, which were mostly based on polysubstituted compounds.Classical shielding mechanisms were evaluated with the program SHIFT, based on force-field-minimized structures.Steric-induced shielding dominates in the hydrocarbon, leading to upfield shifts increasing with the number of 1,3-diaxial interactions.Linear electric-field effects predict, e.g., the shielding difference between equatorial and axial protons vicinal to C-Hal bonds and the deshielding observed for diaxial C-Hal/C-H bond arrangements.A combination of anisotropy and electric-field effects explains all shifts observed in the ketones with the exception of protons vicinal to C=O; a multilinear regression analysis leads to Δχ1C=O = -36 (-27) and Δχ2C=O = -24 (-21) (10-3 cm3/molecule, old ApSimon values in parentheses); it is, however, demonstrated, that an analysis on the basis of NMR shifts alone leads to broad ranges of parameters.Parallels between 1H and 13C NMR shifts are drawn, particularly at γ and θ positions to C-Hal bonds.
- Schneider, Hans-Joerg,Buchheit, Ulrich,Becker, Norman,Schmidt, Guenter,Siehl, Ulrich
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p. 7027 - 7039
(2007/10/02)
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