title: Synthesis and evaluation of substituted chroman-4-one and chromone derivatives as sirtuin 2-selective inhibitors.
abstract: A series of substituted chromone/chroman-4-one derivatives has been synthesized and evaluated as novel inhibitors of SIRT2, an enzyme involved in aging-related diseases, e.g., neurodegenerative disorders. The analogues were efficiently synthesized in a one-step procedure including a base-mediated aldol condensation using microwave irradiation. The most potent compounds, with inhibitory concentrations in the low micromolar range, were substituted in the 2-, 6-, and 8-positions. Larger, electron-withdrawing substituents in the 6- and 8-positions were favorable. The most potent inhibitor of SIRT2 was 6,8-dibromo-2-pentylchroman-4-one with an IC(50) of 1.5 μM. The synthesized compounds show high selectivity toward SIRT2 over SIRT1 and SIRT3 and represent an important starting point for the development of novel SIRT2 inhibitors.
authors: Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden.
authors: Maria
authors: M
authors: Fridén-Saxin
authors: Tina
authors: T
authors: Seifert
authors: Marie Rydén
authors: MR
authors: Landergren
authors: Tiina
authors: T
authors: Suuronen
authors: Maija
authors: M
authors: Lahtela-Kakkonen
authors: Elina M
authors: EM
authors: Jarho
authors: Kristina
authors: K
authors: Luthman
mesh_terms: D002839:Chromans / Q000138:chemical synthesis* / Q000737:chemistry; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry; D002942:Circular Dichroism; D057075:Enzyme Assays; D008968:Molecular Conformation; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002839:Chromans; D002867:Chromones; D056565:Sirtuin 2