RESUMO
Alkyne 40, 5-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylpent-4-yn-2-ol (EC144), is a second generation inhibitor of heat shock protein 90 (Hsp90) and is substantially more potent in vitro and in vivo than the first generation inhibitor 14 (BIIB021) that completed phase II clinical trials. Alkyne 40 is more potent than 14 in an Hsp90α binding assay (IC(50) = 1.1 vs 5.1 nM) as well as in its ability to degrade Her-2 in MCF-7 cells (EC(50) = 14 vs 38 nM). In a mouse model of gastric tumors (N87), 40 stops tumor growth at 5 mg/kg and causes partial tumor regressions at 10 mg/kg (po, qd × 5). Under the same conditions, 14 stops tumor growth only at 120 mg/kg, and does not induce partial regressions. Thus, alkyne 40 is approximately 20-fold more efficacious than 14 in mice.
Assuntos
Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Humanos , Difração de Raios XAssuntos
Benzamidas/farmacologia , Benzoquinonas/farmacologia , Ensaios Clínicos como Assunto , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/farmacologia , Purinas/farmacologia , Resorcinóis/farmacologia , Animais , Benzamidas/síntese química , Benzamidas/química , Benzoquinonas/síntese química , Benzoquinonas/química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/química , Estrutura Molecular , Purinas/síntese química , Purinas/química , Resorcinóis/síntese química , Resorcinóis/química , Relação Estrutura-AtividadeRESUMO
The "aglycone" of pluraflavin A (2) has been synthesized. The key features of this synthesis include a 1,3-dipolar cycloaddition between a nitrile oxide (cf. 14) and an olefin (22) to yield an isoxazoline followed by subsequent conversion into the gamma-pyrone of pluraflavin A. The epoxide moiety linked to the pyrone is installed prior to Diels-Alder installation of the D ring, which allows access to a number of potentially active cytotoxic intermediates en route to the final compound. The preliminary in vitro results of two such compounds are also included with the racemic title compound exhibiting cytotoxicity in the nanomolar range.
Assuntos
Antraquinonas/síntese química , Antraquinonas/química , Antraquinonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , HumanosRESUMO
Syntheses of several unique spironitronates are reported. The key transformation involves the first known example of an ipso oxidative cyclization of nitro functionality. Oxidation proceeds from both o- and p-phenols. Reductions of these compounds provide novel spiroisoxazoline derivatives.
Assuntos
Isoxazóis/síntese química , Resorcinóis/química , Nitrocompostos/química , Fenóis , Compostos de Espiro/químicaRESUMO
[reaction: see text] An efficient regioselective method for oxidation of phenols to o-quinones is reported. When this procedure is combined with a subsequent reduction, it proves to be useful for the construction of a variety of catechols.
