Synthesis and in vitro evaluation of 2-amino-4-N-piperazinyl-6-(3,4-dimethoxyphenyl)-pteridines as dual immunosuppressive and anti-inflammatory agents

Jonghe, Steven De; Marchand, Arnaud; Gao, Ling‐Jie; Calleja, Agnes; Cuveliers, Eva; Sienaert, Ilse; Herman, Jean; Clydesdale, Gavin; Sefrioui, Hassan; Lin, Yuan; Pfleiderer, Wolfgang; Waer, Mark; Herdewijn, Piet

doi:10.1016/j.bmcl.2010.11.053

Cited by 25 publications

(14 citation statements)

References 16 publications

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“…The anti‐inflammatory activities of compounds 34c and 34d were also confirmed in a mouse model of trinitrobenzenesulphonate (TNBS)‐induced colitis used as a model for human Crohn disease, where histological scores, myeloperoxidase (MPO) activity in the colon and anti‐TNBS IgG 1 antibody production were lower after treatment with 34c and 34d . SAR studies performed with this series, its precursors, and related compounds demonstrated that the 6‐(3,4‐dimethoxyphenyl) substituent is essential for the immunosuppressive and anti‐inflammatory activities and that the derivatization of the piperazine moiety as amides or urea strongly lowered the MLR IC 50 to sub‐nM values …”

Section: Anti‐inflammatory Activitymentioning

confidence: 72%

“…A series of 2‐amino‐4‐ N ‐piperazinyl‐6‐(3,4‐dimethoxyphenyl)pteridine analogues were immunosuppressive when used in a mixed lymphocyte reaction (MLR), reaching in some cases nanomolar IC 50 rates (up to 0.5 nM in the case of compound 34a ), as well as when used in in vitro assays with LPS‐stimulated human peripheral blood mononuclear cells, in which they were also able to suppress TNF‐α cell production, with compound 34b reaching the lowest IC 50 (10 nM) . The anti‐inflammatory activities of compounds 34c and 34d were also confirmed in a mouse model of trinitrobenzenesulphonate (TNBS)‐induced colitis used as a model for human Crohn disease, where histological scores, myeloperoxidase (MPO) activity in the colon and anti‐TNBS IgG 1 antibody production were lower after treatment with 34c and 34d .…”

Section: Anti‐inflammatory Activitymentioning

confidence: 99%

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Therapeutic potential of pteridine derivatives: A comprehensive review

Carmona‐Martínez

Ruiz–Alcaraz

Vera

et al. 2018

Medicinal Research Reviews

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Pteridines are aromatic compounds formed by fused pyrazine and pyrimidine rings. Many living organisms synthesize pteridines, where they act as pigments, enzymatic cofactors, or immune system activation molecules. This variety of biological functions has motivated the synthesis of a huge number of pteridine derivatives with the aim of studying their therapeutic potential. This review gathers the state‐of‐the‐art of pteridine derivatives, describing their biological activities and molecular targets. The antitumor activity of pteridine‐based compounds is one of the most studied and advanced therapeutic potentials, for which several molecular targets have been identified. Nevertheless, pteridines are also considered as very promising therapeutics for the treatment of chronic inflammation‐related diseases. On the other hand, many pteridine derivatives have been tested for antimicrobial activities but, although some of them resulted to be active in preliminary assays, a deeper research is needed in this area. Moreover, pteridines may be of use in the treatment of many other diseases, such as diabetes, osteoporosis, ischemia, or neurodegeneration, among others. Thus, the diversity of the biological activities shown by these compounds highlights the promising therapeutic use of pteridine derivatives. Indeed, methotrexate, pralatrexate, and triamterene are Food and Drug Administration approved pteridines, while many others are currently under study in clinical trials.

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Section: Anti‐inflammatory Activitymentioning

confidence: 72%

Section: Anti‐inflammatory Activitymentioning

confidence: 99%

Therapeutic potential of pteridine derivatives: A comprehensive review

Carmona‐Martínez

Ruiz–Alcaraz

Vera

et al. 2018

Medicinal Research Reviews

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“…The importance of pteridines in the key cofactors, tetrahydrofolate and tetrahydrobiopterin, has encouraged the development of the chemistry and chemical biology of pteridines . The pteridine nucleus is found to be essential component of various compounds possessing biological activities such as anti‐inflammatory , antimicrobial , anti‐hepatitis , immunosuppressive , antitumor , and neurodegenerative agents activities as well as α‐tumor nacrosis factor agents , adenosine kinase inhibitors , and nitric oxide synthase inhibitors . Methotrexate ( 1 ) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of New Dipyridylpteridines, Lumazines, and Related Analogues

Abbas

Abu-Mejdad

Atwan

et al. 2016

Journal of Heterocyclic Chem

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Condensation of 4,5‐diaminopyrimidines 2 and 3 with 2,2ʹ‐dipyridil (4) afforded 6,7‐bis(2‐pyridyl)pteridine‐2‐one analogues 5 and 7, respectively. Analogously, 6,7‐bis(2‐pyridyl)luamzine derivatives 13, 15, 17, and 23 were synthesized from reaction of 5,6‐diamino‐2‐thiopyrimidines 13, 14, and 22 with 4, respectively, while condensation of 4,5,6‐triaminopyrimidines (25) or 5,6‐diamino analogue 26 with 4 furnished the 4‐amino‐pteridine analogue 27 and 28, respectively. Thiation of the new pteridines and lumazines afforded the 4‐thio analogues 6, 8, 16, and 24. Treatment of 6 and 8 with methanolic ammonia afforded the 4‐isopterine analogues 9 and 10, respectively. Alkylation of 15 with substituted phenacyl chloride furnished 18 and 19, which cyclized to the thiazolo‐pteridine derivatives 20 and 21, respectively, on treatment with polyphosphoric acid. Alternatively, 27 was prepared from treatment of 24 with methanolic ammonia under drastic conditions. Condensation of 2 or 29 with 2‐oxo‐2‐(thiophen‐2‐yl)acetaldehyde oxime (11) gave the 6‐(2‐thienyl)‐pteridine‐4‐one (12) and 5‐chloro‐2‐(2‐thienyl)pyrido[3,4‐b]pyrazine (31), respectively. All compounds were evaluated for their antiviral activity against the replication of HIV‐1 and HIV‐2 in MT‐4. Some of the synthesized compounds were tested against the bacterial species, Escherichia coli and Staphylococcus aureus, as well as fungal species, Candida tropicalis and Candida albicans.

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“…). These pentacyclic structures have been incorporated into many molecules capable of antifungal and antibacterial activity, HIV protease inhibition and anti‐inflammatory activity . As a direct result of their importance, research on PCUD derivatives continues to the present day .…”

Section: Introductionmentioning

confidence: 99%

Preparation and complete ¹ H and ¹³C assignment of some pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane‐8,11‐dione (PCUD) derivatives

Kenwright

Sellars

2012

Magnetic Reson in Chemistry

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Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. NMR spectra are fully assigned, revealing some general characteristics not previously reported for this class of compound, which should aid the assignment and prediction of the NMR spectra of new PCUD derivatives.

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Synthesis and in vitro evaluation of 2-amino-4-N-piperazinyl-6-(3,4-dimethoxyphenyl)-pteridines as dual immunosuppressive and anti-inflammatory agents

Cited by 25 publications

References 16 publications

Therapeutic potential of pteridine derivatives: A comprehensive review

Therapeutic potential of pteridine derivatives: A comprehensive review

Synthesis and Biological Evaluation of New Dipyridylpteridines, Lumazines, and Related Analogues

Preparation and complete ¹ H and ¹³C assignment of some pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane‐8,11‐dione (PCUD) derivatives

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Synthesis and in vitro evaluation of 2-amino-4-N-piperazinyl-6-(3,4-dimethoxyphenyl)-pteridines as dual immunosuppressive and anti-inflammatory agents

Cited by 25 publications

References 16 publications

Therapeutic potential of pteridine derivatives: A comprehensive review

Therapeutic potential of pteridine derivatives: A comprehensive review

Synthesis and Biological Evaluation of New Dipyridylpteridines, Lumazines, and Related Analogues

Preparation and complete 1 H and 13C assignment of some pentacyclo[5.4.0.02,6.03,10.05,9]undecane‐8,11‐dione (PCUD) derivatives

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Preparation and complete ¹ H and ¹³C assignment of some pentacyclo[5.4.0.0^2,6.0^3,10.0^5,9]undecane‐8,11‐dione (PCUD) derivatives