RESUMO
Organic impurities in compound libraries are known to often cause false-positive signals in screening campaigns for new leads, but organic impurities do not fully account for all false-positive results. We discovered inorganic impurities in our screening library that can also cause positive signals for a variety of targets and/or readout systems, including biochemical and biosensor assays. We investigated in depth the example of zinc for a specific project and in retrospect in various HTS screens at Roche and propose a straightforward counter screen using the chelator TPEN to rule out inhibition caused by zinc.
RESUMO
A new class of bicyclic pyrrolopyrimidine-based Janus kinase 3 (JAK-3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK-3.
Assuntos
Janus Quinase 3/antagonistas & inibidores , Pirimidinas/síntese química , Pirróis/síntese química , Doenças Autoimunes/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Imunidade/efeitos dos fármacos , Janus Quinase 2/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Relação Estrutura-AtividadeRESUMO
A new class of pyrimidine-based Janus tyrosine kinase 3 (JAK3) inhibitors are described. Many of these inhibitors showed low nanomolar activity against JAK3.
Assuntos
Janus Quinase 3/antagonistas & inibidores , Pirimidinas/química , Pirimidinas/farmacologiaRESUMO
The 13-step synthesis of (+)-isoschizandrin reported herein features a samarium(II) iodide-promoted 8-endo ketyl-olefin coupling to assemble the eight-membered ring present in the target concomitantly with the required functionality and stereochemistry. In constructing (+)-isoschizandrin as a single atropisomer, the synthesis utilizes a kinetic resolution of a seven-membered lactone using a CBS-oxazaborolidine.
