RESUMO
Novel pyrano[4,3-b]pyran-5(4H)-one based small molecules were designed as potential inhibitors of sirtuins (i.e., yeast sir2, a homolog of human SIRT1). Elegant synthesis of these compounds was performed via a multi-step sequence consisting of MCR, Sandmeyer type iodination, Sonogashira type coupling followed by iodocyclization and then Pd-mediated various C-C bond forming reactions. The overall strategy involved the construction of a pyran ring followed by the fused pyranone moiety and subsequent functionalization at C-8 position of the resultant core pyrano[4,3-b]pyran-5(4H)-one framework. The crystal structure analysis of a representative iodolactonized product (6d) is presented. Some of the synthesized compounds showed promising inhibitory activities when tested against yeast sir2 in vitro. The compound 6g showed dose dependent inhibition (IC50=78.05µM) of yeast sir2 and good interactions with this protein in silico.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Piranos/química , Proteínas de Saccharomyces cerevisiae/antagonistas & inibidores , Sirtuínas/antagonistas & inibidores , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Isomerismo , Conformação Molecular , Simulação de Acoplamento Molecular , Paládio/química , Ligação Proteica , Piranos/síntese química , Piranos/metabolismo , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/metabolismo , Sirtuínas/metabolismoRESUMO
A new strategy for converting antipsychotic drug olanzapine into PDE4 inhibitors is described via the design and Pd/C mediated synthesis of novel N-indolylmethyl olanzapine derivatives. One compound showed good inhibition (IC50 1.1 µM) and >10 fold selectivity towards PDE4B over D that was supported by docking studies. This compound also showed significant inhibition of TNF-α and no major toxicities in cell lines and a zebrafish embryo model except the teratogenic effects to be re-assessed in rodents.
Assuntos
Antipsicóticos/farmacologia , Benzodiazepinas/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Desenho de Fármacos , Inibidores da Fosfodiesterase 4/síntese química , Inibidores da Fosfodiesterase 4/farmacologia , Antipsicóticos/síntese química , Antipsicóticos/química , Benzodiazepinas/síntese química , Benzodiazepinas/química , Relação Dose-Resposta a Droga , Humanos , Olanzapina , Inibidores da Fosfodiesterase 4/química , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
A new, versatile and direct Pd-mediated method involving intramolecular cyclization of N-(2-iodoaryl)-N-(1-alkyl-1H-indol-2-yl)alkane/arene/heteroarene sulfonamide has been developed leading to a diverse and unique class of indolo[2,3-b]indoles for the potential inhibition of sirtuins.
