发现异喹啉喹唑啉酮类化合物作为一类新型强效过氧化物酶体增殖物激活受体γ拮抗剂，具有抗脂肪生成作用。
Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects.
机构信息
College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.
出版信息
Sci Rep. 2016 Oct 3;6:34661. doi: 10.1038/srep34661.
Conformational change in helix 12 can alter ligand-induced PPARγ activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPARγ antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form hydrogen bonds with the Cys285 and Arg288 residues of PPARγ. Furthermore, SPR results demonstrated strong binding affinity of isoquinolinoquinazolinones towards PPARγ. Additionally, biological assays showed that this new series of PPARγ antagonists more strongly inhibit adipocyte differentiation and PPARγ2-induced transcriptional activity than GW9662.
螺旋 12 构象的变化可以改变配体诱导的 PPARγ 活性；基于这个原因，小檗碱的结构类似物异喹啉喹唑啉酮被设计并合成作为 PPARγ 拮抗剂。计算对接和突变研究表明，异喹啉喹唑啉酮与 PPARγ 的 Cys285 和 Arg288 残基形成氢键。此外，SPR 结果表明异喹啉喹唑啉酮与 PPARγ 具有很强的结合亲和力。此外，生物学测定表明，这一系列新型 PPARγ 拮抗剂比 GW9662 更能强烈抑制脂肪细胞分化和 PPARγ2 诱导的转录活性。
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