基于二肽的2-氧代酰胺作为选择性非钙依赖性磷脂酶A抑制剂。
2-Oxoamides based on dipeptides as selective calcium-independent phospholipase A inhibitors.
作者信息
Smyrniotou Anneta, Kokotou Maroula G, Mouchlis Varnavas D, Barbayianni Efrosini, Kokotos George, Dennis Edward A, Constantinou-Kokotou Violetta
机构信息
Chemical Laboratories, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece.
Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece; Department of Pharmacology and Department of Chemistry and Biochemistry, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0601, USA.
出版信息
Bioorg Med Chem. 2017 Feb 1;25(3):926-940. doi: 10.1016/j.bmc.2016.12.007. Epub 2016 Dec 8.
Calcium-independent phospholipase A (GVIA iPLA) has recently attracted interest as a medicinal target. The number of known GVIA iPLA inhibitors is limited to a handful of synthetic compounds (bromoenol lactone and polyfluoroketones). To expand the chemical diversity, a variety of 2-oxoamides based on dipeptides and ether dipeptides were synthesized and studied for their in vitro inhibitory activity on human GVIA iPLA and their selectivity over the other major intracellular GIVA cPLA and the secreted GV sPLA. Structure-activity relationship studies revealed the first 2-oxoamide derivative (GK317), which presents potent inhibition of GVIA iPLA (X(50) value of 0.007) and at the same time significant selectivity over GIVA cPLA and GV sPLA.
不依赖钙的磷脂酶A（GVIA iPLA）最近作为一个药物靶点引起了人们的关注。已知的GVIA iPLA抑制剂数量仅限于少数几种合成化合物（溴代烯醇内酯和多氟酮）。为了扩大化学多样性，合成了多种基于二肽和醚二肽的2-氧代酰胺，并研究了它们对人GVIA iPLA的体外抑制活性以及对其他主要细胞内GIVA cPLA和分泌型GV sPLA的选择性。构效关系研究揭示了首个2-氧代酰胺衍生物（GK317），它对GVIA iPLA具有强效抑制作用（半数抑制浓度值为0.007），同时对GIVA cPLA和GV sPLA具有显著的选择性。
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