RESUMO
Based on our previous identification of a disubstituted aminothiazole termed HBF-0079 with promising selective toxicity for HCC-derived cell lines versus non-HCC liver lines, a series of tri-substituted aminothiazole derivatives were prepared and evaluated. This work resulted in the discovery of isopropyl 4-(pyrazin-2-yl)-2-(pyrimidin-2-ylamino)thiazole-5-carboxylate, 14, which displayed EC50 value of 0.11µM and more than 450times of selectivity, and its methyl carbonate prodrug 24 with improved solubility in organic solvents. Furthermore, 14, was shown to reduce the proliferation of several liver cancer cells derived directly from patients.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Tiazóis/química , Tiazóis/farmacologia , Aminação , Carbonatos/química , Carbonatos/farmacologia , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Neoplasias Hepáticas/patologia , Pró-Fármacos/química , Pró-Fármacos/farmacologiaRESUMO
Novel N-alkyldeoxynojirimycins (NADNJs) based on our previous lead 3 were designed, synthesized and tested in metabolic assays and in virus cultures. NADNJs containing terminal tertiary benzamide, sulfonamide, urea, and oxazolidinone moieties were discovered to have improved metabolic stability compared to 3, while maintaining submicromolar EC50 against BVDV and Tacaribe virus; and low cytotoxicity.
Assuntos
Antivirais/síntese química , Arenavirus do Novo Mundo/fisiologia , Vírus da Diarreia Viral Bovina/fisiologia , Desenho de Fármacos , Glucosamina/análogos & derivados , 1-Desoxinojirimicina/química , 1-Desoxinojirimicina/metabolismo , 1-Desoxinojirimicina/farmacologia , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Glucosamina/química , Glucosamina/metabolismo , Glucosamina/farmacologia , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Oxazolidinonas/química , Ratos , Sulfonamidas/química , Ureia/química , Replicação Viral/efeitos dos fármacosRESUMO
R7128 is the prodrug of 2'-deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130), a potent and selective inhibitor of HCV NS5B polymerase. Currently, R7128 is in clinical trials for the treatment of HCV infection. To support clinical development efforts, we needed an efficient and scalable synthesis of PSI-6130. We describe an improved, diastereoselective synthetic route starting with protected d-glyceraldehyde. No chiral reagents or catalysts were used to produce the three new contiguous stereocenters. Introduction of fluorine at the C-2 tertiary carbon was accomplished in a highly regio- and stereoselective manner through nucleophilic substitution on a cyclic sulfate. Scale-limiting chromatographic purifications were eliminated through the use of crystalline intermediates.
