RESUMO
The marine alkaloid variolin B 2 and eight synthetic derivatives with different substituents at positions C-5 and C-7 have been tested in a panel of sixteen human tumor cell lines to evaluate their cytotoxic potential.
Assuntos
Alcaloides/síntese química , Antineoplásicos/síntese química , Compostos Aza/síntese química , Guanidinas/síntese química , Pirimidinas/síntese química , Alcaloides/química , Animais , Antineoplásicos/química , Compostos Aza/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Guanidinas/química , Humanos , Poríferos/química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
A total synthesis of the marine alkaloid variolin B has been completed in 13 steps in an overall yield of 6.5% from 3-formyl-4-methoxypyridine. Our approach is based on the sequential formation of the 7-azaindole ring, the tricyclic pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine ring system, and finally installation of the 2-aminopyrimidine ring at C5. The required 7-azaindole ring appropriately substituted is formed by a modified indole synthesis involving a nitrene insertion process (two steps). Formation of the annelated pyrimidine ring is achieved by two routes both involving a carbodiimide-mediated cyclization process, which allow incorporation of the amine functionality at C9 of the core tricyclic (six steps). Installation of the northeast 2-aminopyrimidine ring at C5 is performed using the Bredereck protocol (three steps). Ultimate, thermal decarboxylation with concomitant O-methyl deprotection and further N-benzyl deprotection by the action of triflic acid completed the synthesis of the target natural product variolin B.
