- METHODS AND COMPOSITIONS FOR TREATING AND/OR PREVENTING MUCOSITIS
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Methods for treating and/or preventing mucositis comprising administering to a subject in need thereof an effective amount of at least one compound chosen from E-selectin antagonists, pharmaceutically acceptable salts of E-selectin antagonists, prodrugs of E- selectin antagonists, and pharmaceutically acceptable salts of prodrugs of E-selectin antagonists, and compositions comprising at least one of such compound.
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- Asymmetric palladium-catalyzed allylic alkylation using dialkylzinc reagents: A remarkable ligand effect
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A serendipitously discovered palladium-catalyzed asymmetric allylic alkylation reaction with diorganozinc reagents, which displays broad functional group compatibility, is reported. This novel transformation hinges on a remarkable ligand effect which overrides the standard "umpolung" reactivity of allyl-palladium intermediates in the presence of dialkylzincs. Owing to its mild conditions, enantioselective allylic alkylations of racemic allylic electrophiles are possible in the presence of sensitive functional groups. Umpole-me-not: A serendipitously discovered palladium-catalyzed asymmetric allylic alkylation reaction with diorganozinc reagents displays broad functional group compatibility. This novel transformation hinges on a remarkable ligand effect which overrides the standard "umpolung" reactivity of allyl-palladium intermediates in the presence of dialkylzinc compounds.
- Misale, Antonio,Niyomchon, Supaporn,Luparia, Marco,Maulide, Nuno
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supporting information
p. 7068 - 7073
(2014/07/08)
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- E-SELECTIN ANTAGONIST COMPOUNDS AND METHODS OF USE
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Provided herein are E-selectin antagonist therapeutic agents and improvements thereto and compositions comprising these E-selectin antagonists. Methods are also provided for using these E-selectin antagonist therapeutic agents to treat and/or prevent diseases and disorders treatable by inhibiting binding of an E-selectin to an E-selectin ligand. Also provided herein improvements to E-selectin antagonist giycomimetic compounds that improve the oral bioavailability of the giycomimetic compounds.
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- E-SELECTIN ANTAGONIST COMPOUNDS, COMPOSITIONS, AND METHODS OF USE
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Methods and compositions using E-selectin antagonists are provided for the treatment and prevention of diseases and disorders treatable by inhibiting binding of E-selectin to an E-selectin ligand. Described herein are E-selectin antagonists including, for example, glycomimetic compounds, antibodies, aptamers and peptides that are useful in methods for treatment of cancers, and treatment and prevention of metastasis, inhibiting infiltration of the cancer cells into bone marrow, reducing or inhibiting adhesion of the cancer cells to endothelial cells including cells in bone marrow, and inhibiting thrombus formation. These E-selection antagonists have the general formula (Ia) below.
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- Pre-organization of the core structure of E-selectin antagonists
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A new class of N-acetyl-dglucosamine (GlcNAc) mimics for Eselectin antagonists was designed and synthesized. The mimic consists of a cyclohexane ring substituted with alkyl substituents adjacent to the linking position of the fucose moiety. Incorporation into E-selectin antagonists led to the test compounds 8 and the 2'-benzoylated analogues 21, which exhibit affinities in the low micromolar range. By using saturation transfer difference (STD)-NMR it could be shown that the increase in affinity does not result from an additional hydrophobic contact of the alkyl substituent with the target protein E-selectin, but rather from a steric effect stabilizing the antagonist in its bioactive conformation. The loss of affinity found for antagonists 10 and 35 containing a methyl substituent in a remote position (and therefore unable to support to the stabilization of the core) further supports this hypothesis. Finally, when a GlcNAc mimetic containing two methyl substituents (52 and 53) was used, in which one methyl was positioned adjacent to the fucose linking position and the other was in a remote position, the affinity was regained.
- Schwizer, Daniel,Patton, John T.,Cutting, Brian,Smiesko, Martin,Wagner, Beatrice,Kato, Ako,Weckerle, Celine,Binder, Florian P. C.,Rabbani, Said,Schwardt, Oliver,Magnani, John L.,Ernst, Beat
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supporting information; experimental part
p. 1342 - 1351
(2012/04/04)
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- GLYCOMIMETIC-PEPTIDOMIMETIC INHIBITORS OF E-SELECTINS AND CXCR4 CHEMOKINE RECEPTORS
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Compounds, compositions and methods are provided for treating cancer and inflammatory diseases, and for releasing cells such as stem cells (e.g., bone marrow progenitor cells) into circulating blood and enhancing retention of the cells in the blood. More specifically, glycomimetic-peptidomimetic compounds that inhibit both E-selectins and CXCR4 chemokine receptors are described.
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Page/Page column 60
(2012/05/20)
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- Comparison of the conformational properties of carbasugars and glycosides: The role of the endocyclic oxygen
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A series of carbasugars were prepared and their conformational properties studied by means of NMR spectroscopy. The results were compared to those previously found for O-, S-, and C-β-glycoside analogs. While the rotational populations of the hydroxymethy
- Mayato, Carlos,Dorta, Rosa L.,Palazón, José M.,Vázquez, Jesús T.
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experimental part
p. 101 - 108
(2012/05/04)
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- GLYCOMIMETIC COMPOUNDS AND METHODS TO INHIBIT INFECTION BY HIV
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Compounds, compositions and methods are provided for use to inhibit infection by human immunodeficiency virus (HIV). More specifically, the present invention relates to glycomimetic compounds that inhibit HIV infection, and uses thereof.
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Page/Page column 9
(2011/10/19)
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- HETEROBIFUNCTIONAL INHIBITORS OF E-SELECTINS AND CXCR4 CHEMOKINE RECEPTORS
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Compounds, compositions and methods are provided for treating cancer and inflammatory diseases, and for releasing cells such as stem cells (e.g., bone marrow progenitor cells) into circulating blood and enhancing retention of the cells in the blood. More specifically, heterobifunctional compounds that inhibit both E-selectins and CXCR4 chemokine receptors are described.
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Page/Page column 12; 31
(2010/11/17)
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- Palladium-catalyzed asymmetric synthesis of allylic fluorides
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The enantioselective fluorination of readily available cyclic allylic chlorides with AgF has been accomplished using a Pd(0) catalyst and Trost bisphosphine ligand. The reactions proceed with unprecedented ease of operation for Pd-mediated nucleophilic fluorination, allowing access to highly enantioenriched cyclic allylic fluorides that bear diverse functional groups. Evidence that supports a mechanism in which C-F bond formation occurs by an SN2-type attack of fluoride on a Pd(II)-allyl intermediate is presented.
- Katcher, Matthew H.,Doyle, Abigail G.
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supporting information; experimental part
p. 17402 - 17404
(2011/02/23)
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- GLYCOMIMETIC INHIBITORS OF SIGLEC-8
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Compounds, compositions and methods are provided for detecting or modulating in vitro and in vivo processes mediated by Siglec-8 binding. More specifically, Siglec-8 modulators and their use are described, wherein the Siglec-8 modulators that modulate a S
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Page/Page column 12; 1/3
(2008/06/13)
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- Glycomimetic replacements for hexoses and N-acetyl hexosamines
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Compounds and methods are provided for obtaining oligosaccharide mimics. More specifically, compounds and methods are described wherein oligosaccharide mimics are obtained by incorporating or substituting in a cyclohexane derivative.
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Page/Page column title page; 18
(2008/12/06)
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- Methods of use of glycomimetics with replacements for hexoses and n-acetyl hexosamines
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Methods are provided for using a compound to treat, for example, endothelial dysfunction including vascular abnormalities. More specifically, methods are described for using an oligosaccharide compound or glycomimetic compound wherein a cyclohexane derivative is incorporated in either.
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Page/Page column 25; sheet 1
(2008/12/08)
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- New insights into the mechanism of palladium-catalyzed allylic amination
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A comparative investigation into palladium-catalyzed allylic amination of unsubstituted aziridines and secondary amines has been carried out. The use of NH aziridines as nucleophiles favors formation of valuable branched products in the case of aliphatic allyl acetates. The regioselectivity of this reaction is opposite to that observed when other amines are used as nucleophiles. Our study provides evidence for the palladium-catalyzed isomerization of the branched (kinetic) product formed with common secondary amines into the thermodynamic (linear) product. In contrast, the branched allyl products obtained from unsubstituted aziridines do not undergo the isomerization process. Crossover experiments indicate that the isomerization of branched allylamines is bimolecular and is catalyzed by Pd0. The reaction has significant solvent effect, giving the highest branched-to-linear ratios in THF. This finding can be explained by invoking the intermediacy of σ-complexes, which is consistent with NMR data. The apparent stability of branched allyl aziridines towards palladium-catalyzed isomerization is attributed to a combination of factors that stem from a higher degree of s-character of the aziridine nitrogen compared to other amines. The reaction allows for regio- and enantioselective incorporation of aziridine rings into appropriately functionalized building blocks. The resulting methodology addresses an important issue of forming quaternary carbon centers next to nitrogen. The new insights into the mechanism of palladium-catalyzed allylic amination obtained in this study should facilitate synthesis of complex heterocycles, design of new ligands to control branched-to-linear ratio, as well as absolute stereochemistry of allylamines.
- Watson, Iain D. G.,Yudin, Andrei K.
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p. 17516 - 17529
(2007/10/03)
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- Practical syntheses of enantiopure carbasugars: Carba-β-altrose, carba-β-mannose, carba-β-idose, and carba-β-talose derivatives
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D and L forms of carba-β-altrose 8, carba-β-mannose 10a, carba-β-idose 12, carba-β-talose 14 derivatives were prepared from (±)-3-cyclohexene-1-carboxylic acid 1. Homochiral diol compounds D-5a and L-5a, which were prepared from 1 via enzyme resolution of
- Yu, Seok-Ho,Chung, Sung-Kee
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p. 581 - 584
(2007/10/03)
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- Lipase-silicone biocomposites: Efficient and versatile immobilized biocatalysts
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The last few decades have seen an explosion in the application of enzymes to organic chemistry, as these biological catalysts have continued to demonstrate their unique synthetic capabilities. Despite this, a key prerequisite for establishing enzymes as standard reagents in synthetic chemistry, specifically the availability of generic technologies providing inexpensive, robust, and reusable heterogeneous biological catalysts, still remains to be fulfilled. Herein, we describe a novel and highly efficient immobilization methodology for one of the most utilitarian classes of biocatalysts, namely, lipases. The procedure is based upon the adsorption of crude and pure lipases onto poly(hydroxymethylsiloxane), followed by the incorporation of the formed adsorbates into room-temperature vulcanizable silicones, to form biocatalytic composites. This provides hyperactivated catalysts showing activity enhancements of up to 54-fold as compared with the native enzymes, catalytic densities of up to several hundred kilo-units per gram of immobilizate, and high operational activity and stability in aqueous and organic media. The flexibility of silicone polymer chemistry enables the catalytic biocomposites to be prepared with a variety of physicochemistries, and to be fabricated as solid monoliths, sheets of thick films, particulates, and solid foams, thereby allowing the production of tailored catalysts for a variety of applications. The production and properties of a range of lipase- silicone composites are discussed, and the extended performances of selected catalysts are compared with those of the free enzymes and commercial heterogeneous biocatalysts in model synthetic reactions.
- Gill, Iqbal,Pastor, Eitel,Ballesteros, Antonio
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p. 9487 - 9496
(2007/10/03)
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- Reactions of 1-methoxycarbonyl-3-cyclohexene and 3,4-epoxy-1-methoxycarbonyl-cyclohexane with tert-butoxy radical
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Reactions of 1-methoxycarbonyl-3-cyclohexene and 3,4-epoxy-1-methoxycarbonylcyclohexane (as a 63:37 mixture of trans and cis isomers or pure trans isomers) with tert-butoxy radical at 413 K yield oligomeric products. In the case of epoxy derivatives, 1-methoxycarbonyl-4-cyclohexen-3-ol, 1-methoxycarbonyl-4-cyclohexen-3-one, and 1-methoxycarbonyl-3-cyclohexanone are also formed. This set of products indicates that tert-butoxy radical abstracts a hydrogen atom from the 2-position of the cyclohexene ring and from the 2,3- or 4,5-positions of the cyclohexane ring. 1996 MAEe Cyrillic signΚ Hayκa/Interperiodica Publishing.
- Zaitseva,Narizhnaya
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p. 480 - 485
(2007/10/03)
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- Synthesis of a C22-34 subunit of the immunosuppressant FK-506
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A new route to the C22-34 subunit of FK-506 was developed. A highly diastereoselective Diels-Alder reaction of 1,3-butadiene with the bis-acrylate of (R,R)-hydrobenzoin and subsequent saponification provided the cyclohexenecarboxylic acid 6.4 of 95% ee. Elaboration to the enal 9.2 was effected by known transformations. Enal 9.2 underwent diastereoselective and enantiospecific S(E)2' addition of allenyl stannane (S)-3.9 affording the homopropargylic alcohol 9.3 as an 85:15 syn/anti mixture. The PMB ether 9.5 was converted to the known benzylidene derivative 10.4 by sequential treatment with Red-Al, epoxidation, a second reduction with Red-Al, and oxidative benzylidene formation with DDQ.
- Marshall,Xie
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p. 7230 - 7237
(2007/10/03)
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- Anionic Cycloaddition with Thiophthalides: an Integrated Approach to the Synthesis of Olivin and Pillaromycinone
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A systematic study of the potential reactivity of the thiophthalides 4 and 18 - 20 as 1,4-dipolar synthons, has shown that 3-phenylthiothiophthalide 19 is the best annulating agent for the preparation of tricyclic intermediates related to olivin.The reagent 19 underwent anionic cycloaddition with cyclohex-2-enone 5a in the presence of lithium tert-butoxide to give the anthracenones 24a and 25 in a combined yield of 90percent.
- Majumdar, Gita,Pal, Ranjan,Murty, Kadiyala V. S. N.,Mal, Dipakranjan
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p. 309 - 316
(2007/10/02)
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- Chemoselective Methylation of Caboxylic Acids using DBU and Iodomethane
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Chemoselective methylation of carboxylic acid groups in presence of alcoholic or phenolic hydroxy groups or another carboxylic acid group can be accomplished in high yields using DBU and iodomethane.
- Mal, Dipakranjan
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p. 331 - 336
(2007/10/02)
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- PALLADIUM-CATALYZED CROSS COUPLING OF ALLYL HALIDES WITH ORGANOTIN REAGENTS: A METHOD OF JOINING HIGHLY FUNCTIONALIZED PARTNERS REGIOSELECTIVELY AND STEREOSPECIFICALLY.
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The palladium-catalyzed reaction of allyl halides with aryl- and vinyltin reagents gives high yields of cross-coupled products. In the presence of 1-3 atm of carbon monoxide, ketones are obtained, resulting from cross coupling accompanied by carbon monoxide insertion. The reaction is mild and tolerant of a wide variety of functionalities (OH, OR, CN, CO//2R, CHO) on either the allyl chloride or the tin reagent. Coupling at the allyl halide partner proceeds with inversion of configuration at the carbon bearing the halide, with retention of geometry at the allylic double bond, and with a regioselectivity for the least-substituted carbon in the allylic framework. Retention of double-bond geometry is observed in the vinyltin partner.
- Sheffy,Godschalx,Stille
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p. 4833 - 4840
(2007/10/11)
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- Total Syntheses of (+/-)-Daunomycinone. Regiospecific Preparations of (+/-)-7,9-Dideoxydaunomycinone and 6,11-Dihydroxy-4-methoxy-7,8,9,10-tetrahydronaphthacene-5,9,12-trione
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Regiospecific total syntheses of 7,9-dideoxydaunomycinone (18) and 6,11-dihydroxy-4-methoxy-7,8,9,10-tetrahydonaphthacene-5,9,12-trione (7), late stage precursors to (+/-)-daunomycinone (2a), are described.
- Hauser, Frank M.,Prasanna, Subbarao
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p. 6378 - 6386
(2007/10/02)
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