RESUMEN
Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.
Asunto(s)
Aminoquinolinas/síntesis química , Antiinflamatorios/síntesis química , Apolipoproteína A-I/metabolismo , Benzoatos/síntesis química , Proteínas Nucleares/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Quinolinas/síntesis química , Factores de Transcripción/antagonistas & inhibidores , Aminoquinolinas/farmacocinética , Aminoquinolinas/farmacología , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/farmacología , Benzoatos/farmacocinética , Benzoatos/farmacología , Proteínas de Ciclo Celular , Descubrimiento de Drogas , Humanos , Ratones , Quinolinas/farmacocinética , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
Tributylgermanium hydride (Bu(3)GeH) can be used as an alternative to tributyltin hydride (Bu(3)SnH) as a radical generating reagent with a wide range of radical substrates. Tributylgermanium hydride has several practical advantages over tributyltin hydride, e.g. low toxicity, good stability and much easier work-up of reactions. The reagent can be easily prepared in good yield and stored indefinitely. Suitable substrates include iodides, bromides, activated chlorides, phenyl selenides, tert-nitroalkanes, thiocarbonylimidazolides and Barton esters. Alkyl, vinyl and aryl radicals can be generated in radical reactions including reduction and cyclisation processes. Common radical initiators such as ACCN and triethylborane can be used. The slower rate of hydrogen abstraction by carbon-centred radicals from Bu(3)GeH as compared to Bu(3)SnH facilitates improved cyclisation yields. Polarity reversal catalysis (PRC) with phenylthiol can be used in reactions which generate stable radical intermediates which will not abstract hydrogen from Bu(3)GeH.
