- Selective inhibition of the cellular sodium pump by emicymarin and 14? anhydroxy bufadienolides
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Partial inhibition of the sodium pump (Na/K-ATP-ase) by a circulating inhibitor is known to occur in humans. The objectives of this study were to determine the effects of novel bufadienolides lacking an oxygen at C14 on sodium pumps in human erythrocytes and leucocytes, dog kidney and pig brain and to document the importance of the stereochemistry at C17 on the ability to inhibit these sodium pumps. 14α bufadienolides were weak inhibitors of all preparations studied. 3?-OH,5?,14? bufadienolide produced near-total inhibition of dog kidney and pig brain Na/K-ATP-ase. Over the same concentration range, it maximally inhibited the sodium pump of erythrocytes by 70% and leucocytes by 47%. The inhibition profile induced in the leucocyte sodium pump deviated significantly from the simple sigmoidal relationship present in the other preparations over the 3 × 10-5 to 1 × 10-7 mol/l concentration range. Allo-emicymarin (17α) was confirmed to be a weak inhibitor of the sodium pump/ATP-ase compared with emicymarin (17?) but both were weaker inhibitors of the leucocyte sodium pump than that of the other preparations. Molecules with the C14 in the ? configuration are more efficacious than in the α configuration. In the case of emicymarin, the attachment of the furone at C17 in the α configuration results in substantially weaker inhibitory activity than in the beta configuration, seen in most cardenolides and bufadienolides. Unlike ouabain and bufalin that show no specificity of action in these preparations, 3?- OH,5?,14? bufadienolide selectively inhibits the activity of at least one low-prevalence subset of the leucocyte Na/K-ATP-ase.
- Hilton, Philip J.,McKinnon, William,Gravett, Edward C.,Peron, Jean-Marie R.,Frampton, Christopher M.,Nicholls, M. Gary,Lord, Gwyn
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- Diels-Alder cycloadditions of 3,5-dibromo-2-pyrone: A new ambident diene
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D-A cycloadditions of 3,5-dibromo-2-pyrone were investigated with a series of electronically and sterically distinct dienophiles. Our results showed that it is a highly potent ambident diene, being more reactive and stereoselective than monobromo-2-pyrone
- Cho, Cheon-Gyu,Kim, Yong-Woo,Lim, Young-Kwan,Park, Jung-Sang,Lee, Haiwon,Koo, Sangman
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- A Suzuki coupling approach to bufadienolides
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A high yielding route to bufadienolide type steroids using a novel Suzuki coupling reaction between a range of steroid vinyl triflates and 2-pyrone-5-boronate 11 is presented.
- Gravett, Edward C.,Hilton, Philip J.,Jones, Keith,Romero, Fernando
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- Unified Total Synthesis of Five Bufadienolides
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We report a unified total synthesis of five bufadienolides: bufalin (1), bufogenin B (2), bufotalin (3), vulgarobufotoxin (4), and 3-(N-succinyl argininyl) bufotalin (5). After the steroidal ABCD ring 8 was produced, the D ring was cross-coupled with a 2-pyrone moiety and stereoselectively epoxidized to generate 6. TMSOTf promoted a stereospecific 1,2-hydride shift from 6 to establish the β-oriented 2-pyrone of 19. Functional group manipulations from 19 furnished 1-5, which potently inhibited cancer cell growth.
- Hagiwara, Koichi,Inoue, Masayuki,Itoh, Hiroaki,Shimizu, Shinsuke
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supporting information
(2020/11/13)
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- 3-Bromo-2-Pyrone: An Alternative and Convenient Route to Functionalized Phosphinines
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The facile access to 3-bromo-2-pyrone allows the preparation of 6-bromo-2-trimethylsilyl-phosphinine by a [4+2] cycloaddition with Me3Si-C≡P for the first time. The regioselectivity of this reaction could be verified by means of single crystal X-ray diffraction of the corresponding W0complex. In the presence of ZnBr2and dppp (1,3-bis(diphenylphosphino)propane) as a bidentate ligand, the bromo-phosphinine quantitatively undergoes a Negishi cross-coupling reaction with PhLi that selectively leads to 6-phenyl-2-trimethylsilyl-phosphinine. This heterocycle could again be characterized by means of X-ray diffraction as a W0complex. These results describe a new and convenient route to 2,6-disubstituted phosphinines that makes use of readily available starting materials.
- Habicht, Marija H.,Wossidlo, Friedrich,Weber, Manuela,Müller, Christian
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p. 12877 - 12883
(2016/08/30)
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- The Cephalostatins. 22. Synthesis of bis-steroidal pyrazine pyrones
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Cephalostatin 1 (1), a remarkably strong cancer cell growth inhibitory trisdecacyclic, bis-steroidal pyrazine isolated from the marine tube worm Cephalodiscus gilchristi, continues to be an important target for practical total syntheses and a model for the discovery of less complex structural modifications with promising antineoplastic activity. In the present study, the cephalostatin E and F rings were greatly simplified by replacement at C-17 with an α-pyrone (in 12), typical of the steroidal bufodienolides, and by a dihydro-γ- pyrone (in 16). The synthesis of pyrazine 12 from 5α- dihydrotestosterone (nine steps, 8% overall yield) provided the first route to a bis-bufadienolide pyrazine. Dihydro-γ-pyrone 16 was synthesized in eight steps from ketone 13. While only insignificant cancer cell growth inhibitory activity was found for pyrones 12 and 16, the results provided further support for the necessity of more closely approximating the natural D-F ring system of cephalostatin 1 in order to obtain potent antineoplastic activity.
- Pettit, George R.,Moser, Bryan R.,Mendonca, Ricardo F.,Knight, John C.,Hogan, Fiona
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p. 1063 - 1069
(2012/10/29)
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- Modified Nucleosides for Rna Interference
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The present invention relates to the use of modified nucleotides and single or double stranded oligonucleotides having at least one of said modified nucleotides for performing RNA interference. The modified nucleotides are selected from 6-membered ring containing nucleotides such as hexitol, altritol, O-substituted or O-alkylated altritol, cyclohexenyl, ribo-cyclohexenyl and O-substituted or O-alkylated ribo-cyclohexenyl nucleotides. The present invention also relates to novel modified nucleosides or nucleotides and to the use of the novel modified nucleosides and nucleotides in single or double stranded oligonucleotides for RNA interference, antisense therapy or other applications.
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Page/Page column 21; 22
(2008/12/04)
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- NOVEL BETA-STEROID COMPOUNDS
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The present invention relates to a compound of formula (I). The invention provides the use of the compound in the inhibition of the sodium pump, use of the compound in medicine and particularly in the treatment of heart disease, hypertension, impaired ren
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Page/Page column 20
(2010/11/24)
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- Synthesis and conformational analysis of a ribo-type cyclohexenyl nucleoside
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A straightforward approach to a novel class of ribo-type cyclohexenyl nucleosides is described. An electron-demand Diels-Alder reaction forms the key-step of the chosen synthetic pathway. Although the difference is small, conformational analysis using NMR shows that this nucleoside analogue adopts preferentially an 2H3 conformation (S-type), while the "deoxy" cyclohexenyl analogue has a preference for a C3′ endo conformation (N-type). Analyses of the conformational equilibrium reveal that, in the given experimental conditions, the difference between adenosine and its cyclohexenyl congener resides in their different ΔG values; furthermore, in adenosine, the conformational preference is of enthalpic origin, whereas in the cyclohexenyl congener, the conformational preference is of entropic origin.
- Vijgen, Sara,Nauwelaerts, Koen,Wang, Jing,Van Aerschot, Arthur,Lagoja, Irene,Herdewijn, Piet
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p. 4591 - 4597
(2007/10/03)
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- One step preparation of bromo-2-pyrones via bromo-decarboxylation of 2-pyrone-carboxylic acids
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Synthetically valuable 3-bromo-2-pyrone, 3-bromocoumarin, 5-bromo-2-pyrone, and 3,5-dibromo-2-pyrone were prepared in one step from readily available 2-pyrone-carboxylic acids via bromo-decarboxylation in good to fair yiels.
- Cho, Cheon-Gyu,Park, Jung-Sang,Jung, In-Hak,Lee, Haiwon
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p. 1065 - 1067
(2007/10/03)
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- 5-Bromo-2-pyrone: An easily prepared ambiphilic diene and a synthetic equivalent of 2-pyrone in mild, thermal, Diels-Alder cycloadditions
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5-Bromo-2-pyrone, a solid prepared easily in one-flask according to a new route (eq. 1), has been found to undergo smooth and highly regiocontrolled 2+4-cycloadditions between 25-100°C with both electron-poor and electron-rich dienophiles; subsequent radical debrominations producted halogen-free bicyclic lactones, including a precursor to a vitamin D steroid, thus showing 5-bromo-2-pyrone to be a practical and effective synthetic equivalent of 2-pyrone in thermal Diels-Alder cycloaddition.
- Afarinkia,Posner
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p. 7839 - 7842
(2007/10/02)
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