RESUMEN
( R)-Boc-2-methylproline (3a) was synthesized in good yield with excellent stereochemical control from alanine benzyl ester hydrochloride 11. The process, which is based on a modification of one described by Kawabata, proceeds in four steps and requires no chromatography. The product ( R)-Boc-2-methylproline (3a) was then carried forward in three steps to produce veliparib 1, a poly(ADP-ribose) polymerase inhibitor.
Asunto(s)
Antineoplásicos/farmacología , Bencimidazoles/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Poli(ADP-Ribosa) Polimerasas/metabolismo , Prolina/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Ciclización , Humanos , Estructura Molecular , Inhibidores de Poli(ADP-Ribosa) Polimerasas/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Prolina/análogos & derivados , Prolina/síntesis química , Prolina/químicaRESUMEN
Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.
Asunto(s)
Antivirales/farmacología , Inhibidores Enzimáticos/farmacología , Hepacivirus/efectos de los fármacos , Paladio/química , Sulfonamidas/farmacología , Uracilo/análogos & derivados , Proteínas no Estructurales Virales/antagonistas & inhibidores , 2-Naftilamina , Antivirales/síntesis química , Antivirales/química , Catálisis , Desarrollo de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Hepacivirus/enzimología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Sulfonamidas/síntesis química , Sulfonamidas/química , Uracilo/síntesis química , Uracilo/química , Uracilo/farmacología , Proteínas no Estructurales Virales/metabolismoRESUMEN
To extend the memory of chirality (MOC) methodology to structurally more diverse compounds, the synthesis of 4-hydroxy-alpha-methylprolines was undertaken. Yield and selectivity were very good, with an unexpected reversal in selectivity observed for the cyclization of one adduct with an unprotected hydroxyl.
Asunto(s)
Prolina/análogos & derivados , Prolina/síntesis química , Catálisis , Ciclización , Estructura Molecular , Prolina/química , EstereoisomerismoRESUMEN
Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening. These micromolar hits were rapidly improved to nanomolar leads on the basis of insights from protein crystallography; however, the compounds displayed extensive binding to human serum albumin and had limited activity in cellular assays. Modifications based on structural information on the binding of lead compounds to both MetAP2 and domain III of albumin allowed the identification of compounds with significant improvements in both parameters, which showed good cellular activity in both proliferation and methionine processing assays.