RESUMO
Some pyrazino[1,2-a]indole-1,4-diones, structurally simplified analogues of the natural mycotoxin gliotoxin, have been synthesised and investigated as inhibitors of prenyltransferases; one compound, 3-acetylthio-9-methoxy-2-methyl-2,3-dihydropyrazino[1,2-a]indole-1,4-dione 10 shows slightly greater selectivity (8-fold) for geranylgeranyltransferase type I (GGTase I) than gliotoxin itself.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Gliotoxina/análogos & derivados , Gliotoxina/farmacologia , Indóis/síntese química , Indóis/farmacologia , Pirazinas/síntese química , Pirazinas/farmacologia , Farnesiltranstransferase , Genes ras/genética , Proteínas Recombinantes/síntese química , Proteínas Recombinantes/farmacologia , Relação Estrutura-AtividadeRESUMO
Dirhodium(II) tetraacetate catalysed reaction of the indoline diazo thioamide 8 gives the thioisomünchnone 9, a stable characterisable solid. This masked thiocarbonyl ylide undergoes 1,3-dipolar cycloaddition with N-methylmaleimide and maleic anhydride to give the exo-cycloadducts 10 and 11, characterised by X-ray crystallography. The thioisomünchnone 18, derived from diazo thioamide 17, is an extremely stable crystalline mesoionic system which can be characterised by X-ray crystallography but fails to undergo intramolecular cycloaddition. The related thioisomünchnone 19 can be generated by reaction of indoline-2-thione 7 with bromoacetyl chloride in the presence of triethylamine, and undergoes cycloaddition to give adducts 20 and 21.