title: Synthesis and biological activity of splitomicin analogs targeted at human NAD(+)-dependent histone deacetylases (sirtuins).
abstract: Small molecules interfering with posttranslational modification of histones are of interest as tools to study epigenetic regulation of gene transcription. Specifically, drugs that interfere with histone deacetylation could be useful to induce differentiation, growth arrest as well as apoptotic cell death in tumor cells. One class of histone deacetylases is known as sirtuins some of which (Saccharomyces cerevisiae Sir2) are for example inhibited by the lactone splitomicin leading to telomeric silencing in yeast. However, splitomicin is only a micromolar inhibitor of yeast Sir2 and does not inhibit human subtypes and the lactone is prone to hydrolytic ring opening. In preliminary SAR-studies, splitomicin analogs lacking this hydrolytically labile ring were described as inactive while the naphthalene moiety could successfully be replaced by smaller aromatic rings in a fragment-like dihydrocoumarin. Here we report the synthesis and biological activity of a series of hydrolytically stable analogs with activity against human SIRT1 and 2. These comparatively small compounds characterized by high ligand efficiency are used as a starting point toward the development of specific inhibitors of histone deacetylases from the class of sirtuins.
authors.affiliation: Institute of Pharmacy, Ernst-Moritz-Arndt-University Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489 Greifswald, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Freitag
authors.forename: Jörg
authors.initials: J
authors.lastname: Schemies
authors.forename: Tim
authors.initials: T
authors.lastname: Larsen
authors.forename: Khattab
authors.initials: K
authors.lastname: El Gaghlab
authors.forename: Felix
authors.initials: F
authors.lastname: Schulz
authors.forename: Tobias
authors.initials: T
authors.lastname: Rumpf
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.forename: Andreas
authors.initials: A
authors.lastname: Link
mesh_terms: D016503:Drug Delivery Systems; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009243:NAD / Q000737:chemistry; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D037761:Sirtuins / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D009281:Naphthalenes; D011753:Pyrones; D009243:NAD; C444426:splitomicin; D037761:Sirtuins