β-内酰胺：一类新型的钙非依赖性磷脂酶 A（VIA 组 iPLA）抑制剂，具有抑制β细胞凋亡的能力。
β-Lactones: A Novel Class of Ca-Independent Phospholipase A (Group VIA iPLA) Inhibitors with the Ability To Inhibit β-Cell Apoptosis.
机构信息
Laboratory of Organic Chemistry, Department of Chemistry , National and Kapodistrian University of Athens , Panepistimiopolis, Athens 15771 , Greece.
Department of Chemistry and Biochemistry and Department of Pharmacology, School of Medicine , University of California, San Diego , La Jolla, San Diego , California 92093-0601 , United States.
出版信息
J Med Chem. 2019 Mar 28;62(6):2916-2927. doi: 10.1021/acs.jmedchem.8b01216. Epub 2019 Mar 12.
Ca-independent phospholipase A (GVIA iPLA) has gained increasing interest recently as it has been recognized as a participant in biological processes underlying diabetes development and autoimmune-based neurological disorders. The development of potent GVIA iPLA inhibitors is of great importance because only a few have been reported so far. We present a novel class of GVIA iPLA inhibitors based on the β-lactone ring. This functionality in combination with a four-carbon chain carrying a phenyl group at position-3 and a linear propyl group at position-4 of the lactone ring confers excellent potency. trans-3-(4-Phenylbutyl)-4-propyloxetan-2-one (GK563) was identified as being the most potent GVIA iPLA inhibitor ever reported ( X(50) 0.0000021, IC 1 nM) and also one that is 22 000 times more active against GVIA iPLA than GIVA cPLA. It was found to reduce β-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes.
钙非依赖性磷脂酶 A（GVIA iPLA）作为糖尿病发展和自身免疫性神经紊乱相关生物学过程的参与者，最近引起了越来越多的关注。开发有效的 GVIA iPLA 抑制剂非常重要，因为迄今为止仅报道了少数几种抑制剂。我们提出了一类基于β-内酰胺环的新型 GVIA iPLA 抑制剂。这种功能与在内酯环的 3 位带有苯基和 4 位带有线性丙基的四碳链相结合，赋予了其优异的效力。反式-3-(4-苯基丁基)-4-丙基恶唑烷-2-酮（GK563）被鉴定为迄今为止报道的最有效的 GVIA iPLA 抑制剂（X(50) 0.0000021，IC 1 nM），并且对 GVIA iPLA 的活性比 GIVA cPLA 高 22,000 倍。它被发现可减少促炎细胞因子诱导的β细胞凋亡，这表明它可能有益于对抗 1 型糖尿病等自身免疫性疾病。
Zotero 插件