Synthesis and Evaluation of Substituted Chroman-4-one and Chromone Derivatives as Sirtuin 2-Selective Inhibitors

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• 作者：Maria Frid茅n-Saxin ; Tina Seifert ; Marie Ryd茅n Landergren ; Tiina Suuronen ; Maija Lahtela-Kakkonen ; Elina M. Jarho ; Kristina Luthman
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 23, 2012
• 年：2012
• 卷：55
• 期：16
• 页码：7104-7113
• 全文大小：406K
• 年卷期：v.55,no.16(August 23, 2012)
• ISSN：1520-4804

文摘

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 IC₅₀ of 1.5 渭M. 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.