Synthesis of 6-Substituted 9-Benzyl-8-hydroxypurines with Potential Interferon-Inducing Activity

Kazaoka, Kazunori; Sajiki, Hironao; Hirota, Kosaku

doi:10.1248/cpb.51.608

Cited by 15 publications

(5 citation statements)

References 12 publications

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“…Critical for this work, N -methylation of 26 , to give 27 , is observed to completely ablate TLR7 activity in this series and also results in a modest increase in MTH1 affinity. This observation has previously been reported for a closely related series of TLR7 agonist purinones and indicates that the exocyclic NH 2 motif is critical for TLR7 activity . In a similar fashion, it has been reported that N -methylation of 4 also results in complete loss of TLR7 agonist activity .…”

Section: Resultssupporting

confidence: 81%

Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival

et al. 2016

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Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. MTH1 is one of the "housekeeping" enzymes that are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal and chemically distinct tool compounds to those published in the literature to allow us to test the hypothesis that inhibition of MTH1 has wide applicability in the treatment of cancer. Here we present the work that led to the discovery of three structurally different series of MTH1 inhibitors with excellent potency, selectivity, and proven target engagement in cells. None of these compounds elicited the reported cellular phenotype, and additional siRNA and CRISPR experiments further support these observations. Critically, the difference between the responses of our highly selective inhibitors and published tool compounds suggests that the effect reported for the latter may be due to off-target cytotoxic effects. As a result, we conclude that the role of MTH1 in carcinogenesis and utility of its inhibition is yet to be established.

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Section: Resultssupporting

confidence: 81%

Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival

et al. 2016

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“…In addition to the ability to form water-soluble salts, the 4-piperidinyl moiety of oxoadenines 3a–g also provides a suitable handle for potential N-derivatization and conjugation as substitution of the aromatic amino group in both the oxoadenine and imidazoquinoline series abolishes IFN-inducing activity. 6,17 Conjugation of TLR7/8 agonists to lipids, proteins, and other molecules is known to enhance immune responses and decrease toxic effects. 6,18,19 …”

mentioning

confidence: 99%

Structural requirements for TLR7-selective signaling by 9-(4-piperidinylalkyl)-8-oxoadenine derivatives

Bazin¹,

Li²,

Khalaf³

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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We report the synthesis and biological evaluation of a new series of 8-oxoadenines substituted at the 9-position with a 4-piperidinylalkyl moiety. In vitro evaluation of the piperidinyl-substituted oxoadenines 3a–g in human TLR7- or TLR8-transfected HEK293 cells and in human PBMCs indicated that TLR7/8 selectivity/potency and cytokine induction can be modulated by varying the length of the alkyl linker. Oxoadenine 3f containing a 5-carbon linker was found to be the most potent TLR7 agonist and IFNα inducer in the series whereas 3b possessing a 1-carbon linker was the most potent TLR8 agonist.

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“…The next step of the synthesis consisted of forming the cyclic urea of the purin-8-one skeleton. This was conveniently achieved in quantitative yields by using triphosgene 12 in THF (Scheme 1, 5a,c-g, Table 1). Whereas triphosgene reacted rapidly with the first amino functionality (presumably the more nucleophilic 5-amino substituent) at room temperature to form a non-cyclised intermediate, 13 heating to reflux was required for complete cyclisation into purin-8-ones 5.…”

Section: Figurementioning

confidence: 99%

A General and Facile Route to New Trisubstituted Purin-8-ones

Gaulon¹,

Dijkstra²,

Springer³

2005

Synthesis

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A facile general route was developed to synthesise new trisubstituted purin-8-one derivatives starting from cheap and readily available 5-bromouracil. These fused planar heterocycles present key hydrogen bond donating/accepting functionalities, making them interesting scaffolds for binding to biological targets.Purine derivatives constitute an enormous class of compounds, which are well-known as therapeutic agents. These fused heterocycles show strong binding to various proteins due to their planar structure and their hydrogen bond donating/accepting ability. 1 Purin-8-one or 8-hydroxypurine derivatives for example are reported to possess a wide range of biological activities. Some of them have excellent binding affinity to the corticotropin-releasing hormone (CRH) receptor, a key player in anxiety related disorders. 2 Others stimulate the humoral immune response by binding selectively to B-cells. 3 8-Hydroxypurine derivatives were also reported as potent interferon inducing agents in the treatment of hepatitis C virus, 4 or as cyclin-dependent kinases (CDKs) inhibitors by binding to the ATP pocket of the protein. 5 We were interested in the synthesis of purin-8-ones with the general formula 1 (Figure 1). Only a few examples of this particular family of purine derivatives are known in the literature. 3a,4b,6 To our knowledge, no trisubstituted derivative (R 1 , R 2 and R 3 are different from H) has been reported and only one derivative substituted in the position N-7 (R 1 = n-propyl, R 2 = n-butyl, R 3 = H) was described in a study of potential immunostimulatory purine derivatives. 3a In contrast, the position N-9 (R 2 ) was found to be more diversely substituted by either alcohols and diols (identified as enzymic oxidation intermediates of antiherpetic 6-deoxyacyclovir 6c and famciclovir 6a ), a benzyl functionality 4b or ribosyl groups. 6b,d Two strategies are used in the literature to synthesise these purin-8-ones. In the first, the modification of guanine derivatives 4b,6b,d involved long synthetic pathways and gave low yields. The second more general route involved the construction of the fused heterocyclic skeleton by modification of the pyrimidine derivatives 2-amino-4,6-dichloropyrimidine 3 and 2,4-diaminopyrimidine-5-carboxylic acid. 6e However, these starting materials did not appear suitable for the construction of trisubstituted compounds like 1, as they lead to purin-8-ones in which R 3 = H or R 1 , R 2 and R 3 = H. Therefore, an improved synthetic route was needed in order to access a wide range of trisubstituted purin-8-ones 1. Here, we report a facile and general five-step pathway to synthesise compounds of type 1 (Figure 1) starting from cheap and readily available 5-bromouracil. Figure 1

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Synthesis of 6-Substituted 9-Benzyl-8-hydroxypurines with Potential Interferon-Inducing Activity

Cited by 15 publications

References 12 publications

Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival

Potent and Selective Inhibitors of MTH1 Probe Its Role in Cancer Cell Survival

Structural requirements for TLR7-selective signaling by 9-(4-piperidinylalkyl)-8-oxoadenine derivatives

A General and Facile Route to New Trisubstituted Purin-8-ones

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