RESUMO
A series of aza-5[H]-phenanthridin-6-ones were synthesized and evaluated as inhibitors of poly ADP-ribose polymerase-1 (PARP-1). Inhibitory potency of the unsubstituted aza-5[H]-phenanthridin-6-ones (i.e., benzonaphthyridones) was dependent on the position of the nitrogen atom within the core structure. The A ring nitrogen analogues (7-, 8-, and 10-aza-5[H]-phenanthridin-6-ones) were an order of magnitude less potent than C ring nitrogen analogues (1-, 2-, 3-, and 4-aza-5[H]-phenanthridin-6-ones). Preliminary stroke results from 1- and 2-aza-5[H]-phenanthridin-6-one prompted structure-activity relationships to be established for several 2- and 3-substituted 1-aza-5[H]-phenanthridin-6-ones. The 2-substituted 1-aza-5[H]-phenanthridin-6-ones were designed to improve the solubility and pharmacokinetic profiles for this series of PARP-1 inhibitors. Most importantly, three compounds from this series demonstrated statistically significant protective effects in rat models of stroke and heart ischemia.
Assuntos
Compostos Aza/síntese química , Isquemia Encefálica/tratamento farmacológico , Inibidores Enzimáticos/síntese química , Isquemia Miocárdica/tratamento farmacológico , Naftiridinas/síntese química , Fenantridinas/síntese química , Piperazinas/síntese química , Piperidinas/síntese química , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Compostos Aza/química , Compostos Aza/farmacologia , Cães , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Haplorrinos , Humanos , Técnicas In Vitro , Injeções Intravenosas , Masculino , Microssomos Hepáticos/metabolismo , Naftiridinas/química , Naftiridinas/farmacologia , Fenantridinas/química , Fenantridinas/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Solubilidade , Relação Estrutura-Atividade , Distribuição Tecidual , ÁguaRESUMO
2-Alkyl-substituted butadienes are synthesized starting from a masked butadiene reagent, which allows the regiospecific synthesis of 2-alkylbutadienes by lithiation and subsequent reaction with alkyl halides or aliphatic aldehydes. The regioselectivity of the reaction with allylic halides and aliphatic and aromatic aldehydes is studied.
RESUMO
A wide variety of benzotriazolyl-stabilized anions 2, obtained by the lithiation of 1-(alpha-alkoxyalkyl)-, 1-[alpha-(alkylthio)alkyl]-, and 1-[alpha-(carbazol-9-yl)alkyl]benzotriazoles 1, on reaction with aliphatic and aromatic aldehydes and ketones, followed by rearrangement induced by heating in the presence of zinc bromide, furnish one-carbon-homologated alpha-alkoxyalkyl, alpha-(alkylthio)alkyl, and alpha-(carbazol-9-yl)alkyl ketones 4 in simple one-pot operations in good yields with excellent regioselectivity. In several alkoxymethylene insertions, intermediate 2-alkoxyoxiranes were separated in good yields, demonstrating the epoxide mechanism for the rearrangements and providing a facile approach to polysubstituted 2-alkoxyoxiranes, another class of important compounds.
