- Identification of a Water-Soluble Indirubin Derivative as Potent Inhibitor of Insulin-like Growth Factor 1 Receptor through Structural Modification of the Parent Natural Molecule
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Indirubins have been identified as potent ATP-competitive protein kinase inhibitors. Structural modifications in the 5-and 3′-position have been extensively investigated, but the impact of substituents in 5′-position is not equally well-studied. Here, we report the synthesis of new indirubin 3′-and 5′-derivatives in the search of water-soluble indirubins by introducing basic centers. Antiproliferative activity of all compounds in tumor cells was evaluated along with kinase inhibition of selected compounds. The results show the 3′-position to tolerate large substituents without compromising activity, whereas bulk and rigid substituents in 5′-position appear unfavorable. Screening molecular targets of water-soluble 3′-oxime ethers revealed 6ha as preferential inhibitor of insulin-like growth factor 1 receptor (IGF-1R) in a panel of 22 protein kinases and in cells. Consistently, 6ha inhibited tumor cell growth in the NCI 60 cell line panel and induced apoptosis. The results indicate that the 5′-position provides limited space for chemical modifications and identify 6ha as a potent water-soluble indirubin-based IGF-1R inhibitor.
- Cheng, Xinlai,Merz, Karl-Heinz,Vatter, Sandra,Zeller, Jochen,Muehlbeyer, Stephan,Thommet, Andrea,Christ, Jochen,W?lfl, Stefan,Eisenbrand, Gerhard
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p. 4949 - 4962
(2017/06/28)
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- FUSED HETEROCYCLIC COMPOUND
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A compound of the formula: wherein ring'' A is a 7-membered or 8-membered nitrogen- containing ring optionally further substituted, ring B is an optionally substituted aryl group or an optionally substituted heteroaryl group, X1 is a group represented by -NR3-Y1-, -0-, -S-, -SO-, -SO2- or -CHR3- wherein R3 is a hydrogen atom or'' an optionally substituted aliphatic hydrocarbon group, or R3 may be bonded to the carbon atom of ring B to form an optionally substituted ring structure, and Y1 is a bond or an optionally substituted C1-4 alkylene, R1 is a hydrogen atom, or an optionally substituted group bonded via a carbon atom or a sulfur atom, the formula = shows a single bond or a double bond, when ===R2 is - R2, R2 is a hydrogen atom, or an optionally substituted group bonded via a carbon atom, a nitrogen atom, an oxygen atom or a sulfur atom, and when ===R2 is =R2, R2 is an oxo group, an optionally substituted alkylidene group, or an optionally, substituted imino group.
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Page/Page column 209
(2010/11/28)
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- Substituted oxygen alicyclic compounds, including methods for synthesis thereof
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The invention provides new methods for preparation of cyclic oxygen compounds, including 2,5-disubstituted tetahydrofurans, 2,6-disubstituted tetrahydropyrans, 2,7-disubstituted oxepanes and 2,8-oxocanes. The invention also provides new cyclic oxygen compounds and pharmaceutical compositions and therapeutic methods that comprise such compounds.
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- Methods for synthesis of substituted tetrahydrofuran compound
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The invention includes inter alia new methods for preparation of the pharmaceutically active compound 2-(4-fluorophenoxymethyl)-5-(4-N-hydroxyureidyl-1-butynyl)-tetrahydrofuran and precursors thereof.
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- Deprotection of tetrahydropyranyl ethers with montmorillonite K-10 clay in methanol
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A variety of tetrahydropyranyl (THP) ethers are removed by Montmorillonite K-10 clay in methanol at room temperature to give alcohols. It has been shown that the THP ethers carrying epoxy, methoxymethoxy (MOMO), tertbutyldiphenylsiloxy (TBDP-SO-), acetoxy (AcO-) and benzoyloxy (BzO-) functionalities are stable under the conditions, while the ethers carrying ketal, tertbutyldimethylsioxy (TBSO-) and β,β,β-trichloroethylimidoxy [CCl3C(=NH)O-] functionalities are unstable.
- Taniguchi, Takahiko,Kadota, Kohei,Elazab, Adel S.,Ogasawara, Kunio
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p. 1247 - 1248
(2007/10/03)
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- A synthesis of (-)-tashiromine and formal synthesis of (+)-tashiromine utilizing a highly enantioselective pyrrole/cobaloxime π-cation cyclization
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Cyclization of (5-N-pyrrolyl-2-hydroxypentyl)cobaloxime (13) proceeds by intramolecular electrophilic aromatic substitution of a cobaloxime π-cation onto the pyrrole ring to provide 6-exo cyclization product (14) in 95% yield. This cyclization is highly enantioselective. It is applied to a synthesis of highly enantioenriched (-)-tashiromine, (-)-21, and a formal synthesis of (+)-tashiromine.
- Gage, Jennifer L.,Branchaud, Bruce P.
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p. 7007 - 7010
(2007/10/03)
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- Biocatalytic approaches to both enantiomers of (2R*,3S*)-2-allyloxy-3,4,5,6-tetrahydro-2H-pyran-3-ol
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Both enantiomers of (2R*,3S*)-2-allyloxy-3,4,5,6-tetrahydro-2H-pyran-3-ol, a precursor of chiral auxiliary for asymmetric addition of organometallics, and its analog, (2S,3S)-2-ethoxy-3,4,5,6-tetrahydro-2H-pyran-3-ol were prepared by biocatalytic optical resolutions. Lipase-catalyzed enantioselective acetylation of the racemate in organic solvent worked well with a high enantioseleclivity. Pseudomonas cepacia lipase was most effective (E = 11-17) for the kinetic resolution. Under the optimized condition, the products, (2R,3S)-2-allyloxy-3,4,5,6-tetrahydro-2H-pyran-3-ol and (2S,3S)-2-ethoxy analog with more than 97% e.e. were obtained in 31-45% yield with 52-62% conversion. The enantiomer, (2S,3R)-2-allyloxy compound was secured by two ways. The repetition of the lipase-catalyzed acetylation on partially enantiomerically enriched substrate afforded the acetate with a high e.e. (97%). A newly developed double resolution procedure in one-pot reaction was also successful. In this case, the apparent E value via two steps became as high as 71.Copyright
- Sugai, Takeshi,Ikeda, Hajime,Ohta, Hiromichi
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p. 8123 - 8134
(2007/10/03)
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- An Enantiomerically Pure Epoxyorganolithium Reagent for the Synthesis of Oligo(tetrahydrofurans) by an Epoxide-Cascade Reaction
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Enantiomerically pure oligo(tetrahydrofurans) 17 and 18 have been prepared using an epoxide cascade reaction.The polyepoxide precursors 13 and 14 were synthesized using the enantiomerically pure epoxyorganolithium reagent 3.Thus, addition of 3 to the THF aldehyde 11 gave alcohol 12 with a high Cram selectivity of 95:5.
- Koert, Ulrich,Wagner, Holger,Stein, Matthias
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p. 7629 - 7632
(2007/10/02)
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- Pyrroles as Terminators in Cationic Cyclizations. The Preparation of 5,6,7,8-Tetrahydroindolizidines and 6,7,8,9-Tetrahydro-5H-pyrroloazepines
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N-(Epoxyalkyl)pyrroles 8-13 are readily prepared either by direct pyrrole N-alkylation with either ω-iodo epoxides or ω-iodo-1,2-alkanediol acetonides followed by conversion to the corresponding epoxides.The cyclizations of these N-(epoxyalkyl)pyrroles were examined with a range of Lewis acids providing cyclized products 14 and 16-21 in moderate to excellent yields.The cyclization products 14, 16, and 20 are formally the products of "anti-Markovnikov" attack on the less substituted epoxide terminus.
- Tanis, Steven P.,Raggon, Jeffrey W.
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p. 819 - 827
(2007/10/02)
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