Dr. Reddy's Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India.
Bioorg Med Chem Lett. 2013 Jul 15;23(14):4195-205. doi: 10.1016/j.bmcl.2013.05.014. Epub 2013 May 15.
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.
新型吡喃并[4,3-b]吡喃-5(4H)-酮小分子被设计为潜在的 sirtuins（即酵母 sir2，人类 SIRT1 的同源物）抑制剂。这些化合物的精致合成都通过多步序列进行，包括 MCR、Sandmeyer 型碘化、Sonogashira 型偶联，然后碘环化，然后进行 Pd 介导的各种 C-C 键形成反应。整体策略涉及构建吡喃环，然后构建稠合吡喃酮部分，然后在所得核心吡喃并[4,3-b]吡喃-5(4H)-酮框架的 C-8 位进行功能化。给出了代表性碘代内酯化产物（6d）的晶体结构分析。一些合成化合物在体外对酵母 sir2 表现出有希望的抑制活性。化合物 6g 对酵母 sir2 表现出剂量依赖性抑制（IC50=78.05μM），并在计算机模拟中与该蛋白具有良好的相互作用。
