2-氧代酰胺对IVA组和VIA组磷脂酶A2的差异抑制作用
Differential inhibition of group IVA and group VIA phospholipases A2 by 2-oxoamides.
作者信息
Stephens Daren, Barbayianni Efrosini, Constantinou-Kokotou Violetta, Peristeraki Anna, Six David A, Cooper Jennifer, Harkewicz Richard, Deems Raymond A, Dennis Edward A, Kokotos George
机构信息
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0601, USA.
出版信息
J Med Chem. 2006 May 4;49(9):2821-8. doi: 10.1021/jm050993h.
Abstract
Inhibitors of the Group IVA phospholipase A(2) (GIVA cPLA(2)) and GVIA iPLA(2) are useful tools for defining the roles of these enzymes in cellular signaling and inflammation. We have developed inhibitors of GVIA iPLA(2) building upon the 2-oxoamide backbone that are uncharged, containing ester groups. Although the most potent inhibitors of GVIA iPLA(2) also inhibited GIVA cPLA(2), there were three 2-oxoamide compounds that selectively and weakly inhibited GVIA iPLA(2). We further show that several potent 2-oxoamide inhibitors of GIVA cPLA(2) containing free carboxylic groups (Kokotos et al. J. Med. Chem. 2002, 45, 2891-2893) do not inhibit GVIA iPLA(2) and are, therefore, selective GIVA cPLA(2) inhibitors.
摘要
IVA型磷脂酶A2（GIVA cPLA2）和GVIA型磷脂酶A2（GVIA iPLA2）的抑制剂是确定这些酶在细胞信号传导和炎症中作用的有用工具。我们基于2-氧代酰胺主链开发了GVIA iPLA2的抑制剂，这些抑制剂呈电中性，含有酯基。尽管GVIA iPLA2的最有效抑制剂也抑制GIVA cPLA2，但有三种2-氧代酰胺化合物选择性且微弱地抑制GVIA iPLA2。我们进一步表明，几种含有游离羧基的GIVA cPLA2的强效2-氧代酰胺抑制剂（Kokotos等人，《药物化学杂志》，2002年，45卷，2891 - 2893页）不抑制GVIA iPLA2，因此是选择性的GIVA cPLA2抑制剂。
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本文引用的文献
1
Spinal phospholipase A2 in inflammatory hyperalgesia: role of group IVA cPLA2.
Br J Pharmacol. 2005 Apr;144(7):940-52. doi: 10.1038/sj.bjp.0706116.
2
Catalytic residues of group VIB calcium-independent phospholipase A2 (iPLA2gamma).
Biochem Biophys Res Commun. 2004 Aug 6;320(4):1284-90. doi: 10.1016/j.bbrc.2004.05.225.
3
Inhibition of group IVA cytosolic phospholipase A2 by novel 2-oxoamides in vitro, in cells, and in vivo.
J Med Chem. 2004 Jul 1;47(14):3615-28. doi: 10.1021/jm030485c.
4
In vivo phospholipase activity of the Pseudomonas aeruginosa cytotoxin ExoU and protection of mammalian cells with phospholipase A2 inhibitors.
J Biol Chem. 2003 Oct 17;278(42):41326-32. doi: 10.1074/jbc.M302472200. Epub 2003 Aug 12.
5
The crystal structure, mutagenesis, and activity studies reveal that patatin is a lipid acyl hydrolase with a Ser-Asp catalytic dyad.
Biochemistry. 2003 Jun 10;42(22):6696-708. doi: 10.1021/bi027156r.
6
Novel trifluoromethyl ketones as potent gastric lipase inhibitors.
Chembiochem. 2003 Jan 3;4(1):90-5. doi: 10.1002/cbic.200390019.
7
Ca2+-independent phospholipase A2 is required for agonist-induced Ca2+ sensitization of contraction in vascular smooth muscle.
J Biol Chem. 2003 Jan 17;278(3):1856-63. doi: 10.1074/jbc.M211075200. Epub 2002 Nov 5.
8
Role of an endoplasmic reticulum Ca(2+)-independent phospholipase A(2) in oxidant-induced renal cell death.
Am J Physiol Renal Physiol. 2002 Sep;283(3):F492-8. doi: 10.1152/ajprenal.00022.2002.
9
Synthesis of lipophilic aldehydes and study of their inhibition effect on human digestive lipases.
Org Lett. 2002 Aug 8;4(16):2625-8. doi: 10.1021/ol026039l.
10
Identification of calcium-independent phospholipase A2 (iPLA2) beta, and not iPLA2gamma, as the mediator of arginine vasopressin-induced arachidonic acid release in A-10 smooth muscle cells. Enantioselective mechanism-based discrimination of mammalian iPLA2s.
J Biol Chem. 2002 Sep 6;277(36):32807-14. doi: 10.1074/jbc.M202568200. Epub 2002 Jun 27.
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