2-Oxoamides based on dipeptides as selective calcium-independent phospholipase A₂ inhibitors

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• 作者：Anneta Smyrniotou^a ; Maroula G. Kokotou^b ; ^c ; Varnavas D. Mouchlis^c ; Efrosini Barbayianni^b ; George Kokotos^b ; Edward A. Dennis^c ; ^{edennis@ucsd.edu} ; Violetta Constantinou-Kokotou^a ; ^vikon@aua.gr
• 关键词：Dipeptides ; Inhibitors ; Oxoamides ; Phospholipase A2 ; Pseudodipeptides
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：926-940
• 全文大小：2864 K
• 卷排序：25

文摘

Calcium-independent phospholipase A2 (GVIA iPLA2) has recently attracted interest as a medicinal target. The number of known GVIA iPLA2 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 iPLA2 and their selectivity over the other major intracellular GIVA cPLA2 and the secreted GV sPLA2. Structure-activity relationship studies revealed the first 2-oxoamide derivative (GK317), which presents potent inhibition of GVIA iPLA2 (XI(50) value of 0.007) and at the same time significant selectivity over GIVA cPLA2 and GV sPLA2.