Synthesis and biological evaluation of 2,8-disubstituted 9-benzyladenines: discovery of 8-mercaptoadenines as potent interferon-inducers

Hirota, Kosaku; Kazaoka, Kazunori; Sajiki, Hironao

doi:10.1016/s0968-0896(03)00234-7

Cited by 18 publications

(8 citation statements)

References 21 publications

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“…1a-c). The structure-activity relationships (SAR) of the 8-OAs indicated that both 6-amino and 8-oxo groups were important in TLR7 agonism 19 (Fig. 1a), but the 8-oxo group was too far to interact with TLR7 protein, resulting in a space in which other substituents might be introduced (Fig.…”

Section: Resultsmentioning

confidence: 99%

Structural analysis reveals TLR7 dynamics underlying antagonism

et al. 2020

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Toll-like receptor 7 (TLR7) recognizes both microbial and endogenous RNAs and nucleosides. Aberrant activation of TLR7 has been implicated in several autoimmune diseases including systemic lupus erythematosus (SLE). Here, by modifying potent TLR7 agonists, we develop a series of TLR7-specific antagonists as promising therapeutic agents for SLE. These compounds protect mice against lethal autoimmunity. Combining crystallography and cryo-electron microscopy, we identify the open conformation of the receptor and reveal the structural equilibrium between open and closed conformations that underlies TLR7 antagonism, as well as the detailed mechanism by which TLR7-specific antagonists bind to their binding pocket in TLR7. Our work provides small-molecule TLR7-specific antagonists and suggests the TLR7-targeting strategy for treating autoimmune diseases.

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Section: Resultsmentioning

confidence: 99%

Structural analysis reveals TLR7 dynamics underlying antagonism

et al. 2020

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“…[26] Whereas the benzyl halide led mainly to a single N-9 alkylation product, [27] 1-iododecane or 1-iodoethane, presumably due to their lower steric hindrance, produced mixtures of N-7 and N-9 substituted products in an approximate 1:4 ratio, although the overall yields were still very satisfactory.…”

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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“…Additionally, the difference in the nucleophilicity of the amine groups in intermediate 59 was exploited to furnish, through reductive alkylation, mono-substituted derivatives 61 – 64 with ethyl, n -octyl, n -butyl, and isobutyl groups, respectively (see Scheme 2). 24 The yields in this step were moderate (48, 29, 57, and 52%, respectively) due to incomplete reactions and decomposition of the alkyl aldehyde components. Desilylation (TBAF) of these products afforded compounds 19–21 and 23 in good yields.…”

Section: Resultsmentioning

confidence: 95%

Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues

Nicolaou

Ellery

Rivas

et al. 2011

Bioorganic & Medicinal Chemistry

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Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2′,4′- and 3′,4′-bridged nucleoside analogues was synthesized, including a novel 3′,4′-carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2′,4′-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC50 = 7.0 μM) and HxB2 (IC50 = 2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.

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Synthesis and biological evaluation of 2,8-disubstituted 9-benzyladenines: discovery of 8-mercaptoadenines as potent interferon-inducers

Cited by 18 publications

References 21 publications

Structural analysis reveals TLR7 dynamics underlying antagonism

Structural analysis reveals TLR7 dynamics underlying antagonism

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

Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues

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Synthesis and biological evaluation of 2,8-disubstituted 9-benzyladenines: discovery of 8-mercaptoadenines as potent interferon-inducers

Cited by 18 publications

References 21 publications

Structural analysis reveals TLR7 dynamics underlying antagonism

Structural analysis reveals TLR7 dynamics underlying antagonism

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

Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues

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