ABSTRACT
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.
Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Pyrans/chemistry , Saccharomyces cerevisiae Proteins/antagonists & inhibitors , Sirtuins/antagonists & inhibitors , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Isomerism , Molecular Conformation , Molecular Docking Simulation , Palladium/chemistry , Protein Binding , Pyrans/chemical synthesis , Pyrans/metabolism , Saccharomyces cerevisiae/enzymology , Saccharomyces cerevisiae Proteins/metabolism , Sirtuins/metabolismABSTRACT
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.
Subject(s)
Antipsychotic Agents/pharmacology , Benzodiazepines/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Drug Design , Phosphodiesterase 4 Inhibitors/chemical synthesis , Phosphodiesterase 4 Inhibitors/pharmacology , Antipsychotic Agents/chemical synthesis , Antipsychotic Agents/chemistry , Benzodiazepines/chemical synthesis , Benzodiazepines/chemistry , Dose-Response Relationship, Drug , Humans , Olanzapine , Phosphodiesterase 4 Inhibitors/chemistry , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
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.
