title: Construction and functionalization of pyranone ring fused with pyran moiety: design and synthesis of novel pyrano[4,3-b]pyran-5(4H)-ones as potential inhibitors of sirtuins.
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.
authors.affiliation: Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.
authors.forename: Ali
authors.initials: A
authors.lastname: Nakhi
authors.forename: Md Shafiqur
authors.initials: MS
authors.lastname: Rahman
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Archana
authors.forename: Ravada
authors.initials: R
authors.lastname: Kishore
authors.forename: G P K
authors.initials: GP
authors.lastname: Seerapu
authors.forename: K Lalith
authors.initials: KL
authors.lastname: Kumar
authors.forename: Devyani
authors.initials: D
authors.lastname: Haldar
authors.forename: Manojit
authors.initials: M
authors.lastname: Pal
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D007536:Isomerism; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D010165:Palladium / Q000737:chemistry; D011485:Protein Binding; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011714:Pyrans; D029701:Saccharomyces cerevisiae Proteins; D010165:Palladium; D037761:Sirtuins