- COMPOSITIONS AND METHODS OF MODULATING THE IMMUNE RESPONSE BY ACTIVATING ALPHA PROTEIN KINASE 1
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The disclosure provides compositions and methods related to activating alpha-kinase 1 (ALPK1) for modulating an immune response and treating or preventing cancer, infection, inflammation and related diseases and disorders as well as potentiating an immune response to a target antigen. The disclosure also provides heterocyclic compounds of formula (I) as agonists of alpha protein kinase 1 (ALPK1) and their use in activating ALPK1, modulating an immune response and treating diseases such as cancer, wherein A1, A2, L1, L2, L3, Z1, Z2, W1, W2, R1, R2, R3, R4, R5, R6 and R7 are defined herein.
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- Oligonucleotide analogues with integrated bases and backbones. Part 24: Synthesis, conformational analysis, and association of aminomethylene-linked self-complementary adenosine and uridine dinucleosides
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Inspection of Maruzen models and force-field calculations suggest that oligonucleotide analogues integrating backbone and bases (ONIBs) with an aminomethylene linker form similar cyclic duplexes as the analogous oxymethylene linked dinucleosides. The self
- Chiesa, Katja,Shvoryna, Alyena,Bernet, Bruno,Vasella, Andrea
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scheme or table
p. 668 - 691
(2010/07/07)
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- Oligonucleotide analogues with integrated bases and backbone Part 17 1. Conformational analysis and association of ethylene-, oxymethylene-, and thiomethylene-linked self-complementary adenosine and uridine dimers
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The formation of cyclic duplexes (pairing) of known oxymethylene-linked self-complementary U*[o]A(*) dinucleosides contrasts with the absence of pairing of the ethylene-linked U*[ca]A(*) analogues. The origin of this difference, and the expected association of U*[x]A(*) and A*[x]U(*) dinucleosides with x=CH 2, O, or S was analysed. According to this analysis, pairing occurs via constitutionally isomeric Watson - Crick, reverse Watson - Crick, Hoogsteen, or reverse Hoogsteen H-bonded linear duplexes. Each one of them may give rise to three diastereoisomeric cyclic duplexes, and each one of them can adopt three main conformations. The relative stability of all conformers with x=CH 2, O, or S were analysed. U*[x]A(*) dinucleosides with x=CH2 do not form stable cyclic duplexes, dinucleosides with x=O may form cyclic duplexes with a gg-conformation about the C(4′)-C(5′) bond, and dinucleosides with x=S may form cyclic duplexes with a gt-conformation about this bond. The temperature dependence of the chemical shift of H-N(3) of the self-complementary, oxymethylene-linked U*[o]A(*) dinucleosides 1-6 in CDCl3 in the concentration range of 0.4-50 mM evidences equilibria between the monoplex, mainly linear duplexes, and higher associates for 3, between the monoplex and cyclic duplexes for 6, and between the monoplex, linear, and cyclic duplexes as well as higher associates for 1, 2, 4, and 5. The self-complementary, thiomethylene-linked U*[s]A(*) dinucleosides 27-32 and the sequence isomeric A*[s]U(*) analogues 33-38 were prepared by S-alkylation of the 6-(mesyloxymethyl)uridine 12 and the 8-(bromomethyl)adenosine 22. The required thiolates were prepared in situ from the C(5′)-acetylthio derivatives 9, 15, 19, and 25. The association in CHCl3 of the thiomethylene-linked dinucleoside analogues was studied by 1H-NMR and CD spectroscopy, and by vapour-pressure osmometric determination of the apparent molecular mass. The U*[s]A(*) alcohols 28, 30, and 31 form cyclic duplexes connected by Watson - Crick H-bonds, while the fully protected dimers 27 and 29 form mainly linear duplexes and higher associates. The diol 32 forms mainly cyclic duplexes in solution and corrugated ribbons in the solid state. The nucleobases of crystalline 32 form reverse Hoogsteen H-bonds, and the resulting ribbons are cross-linked by H-bonds between HOCH 2-C(8/I) and N(3/I). Among the A*[s]U(*) dimers, only the C(8/I)-hydroxymethylated 37 forms (mainly) a cyclic duplex, characterized by reverse Hoogsteen base pairing. The dimers 34-36 form mainly linear duplexes and higher associates. Dimers 34 and particularly 38 gelate CHCl3. Temperature-dependent CD spectra of 28, 30, 31, and 37 evidence π-stacking in the cyclic duplexes. Base stacking in the particularly strongly associating diol 32 in CHCl3 solution is evidenced by a melting temperature of ca. 2°.
- Ritter, Anne,Egli, Daniel,Bernet, Bruno,Vasella, Andrea
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experimental part
p. 673 - 714
(2009/02/07)
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- Determinants of cofactor binding to DNA methyltransferases: Insights from a systematic series of structural variants of S-adenosylhomocysteine
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S-Adenosylmethionine (AdoMet) is a commonly used cofactor, second only to ATP in the variety of reactions in which it participates. It is the methyl donor in the majority of methyl transfer reactions, including methylation of DNA, RNA, proteins and small molecules. Almost all structurally characterised methyltransferases share a conserved AdoMet-dependent methyltransferase fold, in which AdoMet is bound in the same orientation. Although potential interactions between the cofactor and methyltransferases have been inferred from crystal structures, there has not been a systematic study of the contributions of each functional group to binding. To explore the binding interaction we synthesised a series of seven analogues of the methyltransferase inhibitor S-adenosylhomocysteine (AdoHcy), each containing a single modification, and tested them for the ability to inhibit methylation by HhaI and HaeIII DNA methyltransferase. Comparison of the Ki values highlights the structural determinants for cofactor binding, and indicates which nucleoside and amino acid functional groups contribute significantly to AdoMet binding. An understanding of the binding of AdoHyc to methyltransferases will greatly assist the design of AdoMet inhibitors.
- Cohen, Helen M.,Griffiths, Andrew D.,Tawfik, Dan S.,Loakes, David
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p. 152 - 161
(2007/10/03)
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- Deamination of 5′-substituted-2′,3′-isopropylidene adenosine derivatives catalyzed by adenosine deaminase (ADA, EC 3.5.4.4) and complementary enzymatic biotransformations catalyzed by adenylate deaminase (AMPDA, EC 3.5.4.6): A viable route for the preparation of 5′-substituted inosine derivatives
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Adenosine deaminase (ADA) catalyzes the deamination of 2′,3′-isopropylidene adenosine and the corresponding 5′-amino derivative in a 3% dimethylsulfoxide aqueous solution. Whereas ADA is unable to convert other 5′-substituted derivatives (acetate, acetamido, azide), the enzyme adenylate deaminase (AMPDA) accepts all the above compounds as substrates for their biotransformation to the corresponding 5′-substituted inosine derivatives.
- Ciuffreda, Pierangela,Loseto, Angela,Santaniello, Enzo
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p. 5767 - 5771
(2007/10/03)
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