RESUMO
Significant effort is being made to understand the role of HDAC isotypes in human cancer and to develop antitumor agents with better therapeutic windows. A part of this endeavor was the exploration of the 14 A internal cavity adjacent to the enzyme catalytic site, which led to the design and synthesis of compound 4 with the unusual bis(aryl)-type pharmacophore. SAR studies around this lead resulted in optimization to potent, selective, nonhydroxamic acid HDAC inhibitors.
Assuntos
Antineoplásicos/síntese química , Benzamidas/síntese química , Inibidores de Histona Desacetilases , NADH NADPH Oxirredutases/antagonistas & inibidores , Antineoplásicos/química , Benzamidas/química , Benzamidas/farmacologia , Domínio Catalítico , Linhagem Celular , Histona Desacetilase 1 , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Modelos Moleculares , NADH NADPH Oxirredutases/química , NADH NADPH Oxirredutases/metabolismo , Relação Estrutura-AtividadeRESUMO
A new strategy for the aryl annulation of cyclic ketones is described. Palladium(0) coupling of a propargyl alcohol with the enol triflate of a ketone and addition of vinylmagnesium chloride generates a triene as a magnesium chelate that may be quenched with an electrophile. In some cases, the triene cyclizes under the reaction conditions. Aromatization is accomplished by exposure to manganese dioxide or dichlorodicyanoquinone (DDQ). [reaction: see text]
RESUMO
[reaction: see text] The synthesis of various tetrasubstituted alkenes and dienes in a regio- and stereocontrolled manner is described. This three-component coupling strategy involves the addition of Grignard reagents to propargyl alcohols followed by palladium(0)-mediated cross-coupling with aryl or vinyl halides. This protocol has been applied to the synthesis of (Z)-Tamoxifen and related mimics.