Synthesis and structure–Activity relationships of 2-Amino-8-hydroxyadenines as orally active interferon inducing agents

Kurimoto, Ayumu; Ogino, Tetsuhiro; Ichii, Shinji; Isobe, Yoshiaki; Tobe, Masanori; Ogita, Haruhisa; Takaku, Haruo; Sajiki, Hironao; Hirota, Kosaku; Kawakami, Hajime

doi:10.1016/j.bmc.2003.09.032

Cited by 37 publications

(31 citation statements)

References 21 publications

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“…Recently, a series of synthetic 8-hydroxyadenines as novel in vitro and in vivo IFN-␣-inducing agents in experimental animals has been reported (20). We showed that one of these compounds, 2-butoxy-8-hydroxy-9-benzyladenine, called SA-2, stimulates high production of proinflammatory and regulatory cytokines and chemokines by human BDCA-4 ϩ plasmacytoid DCs and CD14 ϩ cells.…”

Section: Discussionmentioning

confidence: 91%

“…The present study addressed the in vivo role of SA-2 as a synthetic adjuvant in regulating Th2-mediated airway inflammation by using protocols A and B in OVA-immunized and i.t.-challenged mice. Previous data indicated that SA-2 was able to induce IFN-␣ production both in vitro and in vivo (20,21), but the direct evidence of its interaction with any of murine TLRs was lacking. Our data with a TLR-transfected cell line provide the first demonstration that SA-2 triggers the activation of murine TLR7, as shown by enhanced NF-B-dependent luciferase activity.…”

Section: Discussionmentioning

confidence: 99%

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Modified Adenine (9-Benzyl-2-Butoxy-8-Hydroxyadenine) Redirects Th2-Mediated Murine Lung Inflammation by Triggering TLR7

Vultaggio¹,

Nencini²,

Fitch

et al. 2009

The Journal of Immunology

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Substitute adenine (SA)-2, a synthetic heterocycle chemically related to adenine with substitutions in positions 9-, 2-, and 8- (i.e., 9-benzyl-2-butoxy-8-hydroxyadenine), induces in vitro immunodeviation of Th2 cells to a Th0/Th1 phenotype. In this article, we evaluate the in vivo ability of SA-2 to affect Th2-mediated lung inflammation and its safety. TLR triggering and NF-κB activation by SA-2 were analyzed on TLR-transfected HEK293 cells and on purified bone marrow dendritic cells. The in vivo effect of SA-2 on experimental airway inflammation was evaluated in both prepriming and prechallenge protocols by analyzing lung inflammation, including tissue eosinophilia and goblet cell hyperplasia, bronchoalveolar lavage fluid cell types, and the functional profile of Ag-specific T cells from draining lymph nodes and spleens. SA-2 induced mRNA expression and production of proinflammatory (IL-6, IL-12, and IL-27) and regulatory (IL-10) cytokines and chemokines (CXCL10) in dendritic cells but down-regulated TGF-β. Prepriming administration of SA-2 inhibited OVA-specific Abs and Th2-driven lung inflammation, including tissue eosinophilia and goblet cells, with a prevalent Foxp3-independent regulatory mechanism. Prechallenge treatment with SA-2 reduced the lung inflammation through the induction of a prevalent Th1-related mechanism. In this model the activity of SA-2 was route-independent, but adjuvant- and Ag dose-dependent. SA-2-treated mice did not develop any increase of serum antinuclear autoantibodies. In conclusion, critical substitutions in the adenine backbone creates a novel synthetic TLR7 ligand that shows the ability to ameliorate Th2-mediated airway inflammation by a complex mechanism, involving Th1 redirection and cytokine-mediated regulation, which prevents autoreactivity.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Modified Adenine (9-Benzyl-2-Butoxy-8-Hydroxyadenine) Redirects Th2-Mediated Murine Lung Inflammation by Triggering TLR7

Vultaggio¹,

Nencini²,

Fitch

et al. 2009

The Journal of Immunology

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“…Compound G13 was thus synthesized in 80% yield in the presence of isobutyric anhydride. [33] This product could be halogenated in the presence of bromine and sodium acetate [34] leading to G12 in good yields. Direct attempts to perform a Sonogashira reaction with TMSA on compound G12 were unsuccessful in our hands, despite a related procedure was reported recently from similar substrates, [35] and the starting material was recovered instead.…”

Section: Synthesis Of Pyrimidinesmentioning

confidence: 99%

Synthesis of 5‐/8‐Halogenated or Ethynylated Lipophilic Nucleobases as Potential Synthetic Intermediates for Supramolecular Chemistry

et al. 2015

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El acceso a la versión del editor puede requerir la suscripción del recurso Access to the published version may require subscription Synthesis of 5-/8-Halogenated or Ethynylated Lipophilic Nucleobases as Potential Synthetic Intermediates for Supramolecular ChemistryNerea Bilbao, [a] Violeta Vázquez-González, [a] M. Teresa Aranda, [a] and David González-Rodríguez* [a] Abstract: A series of lipophilic nucleobases that are substituted at the 5-(pyrimidines) or 8-position (purines) with either a halogen atom or a terminal triple bond have been synthesized. The sequences and reactions studied in this work, which mainly comprise halogenation, alkylation, Sonogashira coupling, and trimethylsilylacetylene deprotection, have been carefully optimized in order to reach the final compounds in the most straightforward, convenient way and with the maximum purity and yield. These compounds include cytosine, isocytosine and uracil as pyrimidine heterocycles, and guanine, isoguanine, and 2-aminoadenine as complementary purine bases.Variability was introduced at the N-1/N-9 positions of these pyrimidine/purine nucleobases, which were functionalized with alkyl or benzyl groups, as well as with protected amine or carboxylic acid substituents. The molecules prepared constitute a useful collection of synthetic intermediates in the field of chemical self-assembly.

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“…2 A). Various 8-hydroxyadenine analogs were reported recently to be potent inducers of type I IFNs (21). By genetic complementation in HEK293 cells, we identified SM360320 as a specific TLR7 ligand (Fig.…”

Section: Tlr7mentioning

confidence: 82%

“…A recent report suggested that ribavirin could induce IRF-7 in cells infected with respiratory syncitial virus (21). This finding implied that IMPDH inhibitors might augment the antiviral activity of drugs that similarly induce IRF signaling.…”

mentioning

confidence: 97%

Activation of anti-hepatitis C virus responses via Toll-like receptor 7

Lee

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

187

163

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Synthesis and structure–Activity relationships of 2-Amino-8-hydroxyadenines as orally active interferon inducing agents

Cited by 37 publications

References 21 publications

Modified Adenine (9-Benzyl-2-Butoxy-8-Hydroxyadenine) Redirects Th2-Mediated Murine Lung Inflammation by Triggering TLR7

Modified Adenine (9-Benzyl-2-Butoxy-8-Hydroxyadenine) Redirects Th2-Mediated Murine Lung Inflammation by Triggering TLR7

Synthesis of 5‐/8‐Halogenated or Ethynylated Lipophilic Nucleobases as Potential Synthetic Intermediates for Supramolecular Chemistry

Activation of anti-hepatitis C virus responses via Toll-like receptor 7

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Synthesis and structure–Activity relationships of 2-Amino-8-hydroxyadenines as orally active interferon inducing agents

Cited by 37 publications

References 21 publications

Modified Adenine (9-Benzyl-2-Butoxy-8-Hydroxyadenine) Redirects Th2-Mediated Murine Lung Inflammation by Triggering TLR7

Modified Adenine (9-Benzyl-2-Butoxy-8-Hydroxyadenine) Redirects Th2-Mediated Murine Lung Inflammation by Triggering TLR7

Synthesis of 5‐/8‐Halogenated or Ethynylated Lipophilic Nucleobases as Potential Synthetic Intermediates for Supramolec­ular Chemistry

Activation of anti-hepatitis C virus responses via Toll-like receptor 7

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Product

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Synthesis of 5‐/8‐Halogenated or Ethynylated Lipophilic Nucleobases as Potential Synthetic Intermediates for Supramolecular Chemistry