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1.
Angew Chem Int Ed Engl ; 61(32): e202205231, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35612562

RESUMO

Interferons (IFN) are cytokines which, upon binding to cell surface receptors, trigger a series of downstream biochemical events including Janus Kinase (JAK) activation, phosphorylation of Signal Transducer and Activator of Transcription protein (STAT), translocation of pSTAT to the nucleus and transcriptional activation. Dysregulated IFN signalling has been linked to cancer progression and auto-immune diseases. Here, we report the serendipitous discovery of a small molecule that blocks IFNγ activation of JAK-STAT signalling. Further lead optimisation gave rise to a potent and more selective analogue that exerts its activity by a mechanism consistent with direct IFNγ targeting in vitro, which reduces bleeding in model of haemorrhagic colitis in vivo. This first-in-class small molecule also inhibits type I and III IFN-induced STAT phosphorylation in vitro. Our work provides the basis for the development of pan-IFN inhibitory drugs.


Assuntos
Interferons , Janus Quinases , Interferon gama , Interferons/metabolismo , Interferons/farmacologia , Fosforilação , Transdução de Sinais
2.
Nat Prod Rep ; 37(11): 1478-1496, 2020 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-32808003

RESUMO

Covering: 2000 to 2020 The hallucinogenic diterpene salvinorin A potently and selectively agonizes the human kappa-opioid receptor (KOR). Its unique attributes-lack of a basic nitrogen, rapid brain penetrance, short half-life-combined with the potential of KOR as an emerging target for analgesics have stimulated extensive medicinal chemistry based on semi-synthesis from extracts of Salvia divinorum. Total synthesis efforts have delivered multiple, orthogonal routes to salvinorin A, its congeners and related analogs with the goal of optimizing its activity towards multiple functional endpoints. Here we review total syntheses of the salvinorin chemotype and discuss outstanding problems that synthesis can address in the future.


Assuntos
Diterpenos Clerodânicos/farmacologia , Receptores Opioides kappa/agonistas , Animais , Diterpenos Clerodânicos/química , Humanos , Estrutura Molecular , Salvia/química
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