Anneta Smyrniotou1, Maroula G Kokotou2, Varnavas D Mouchlis3, Efrosini Barbayianni4, George Kokotos4, Edward A Dennis5, Violetta Constantinou-Kokotou6. 1. Chemical Laboratories, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece. 2. 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. 3. Department of Pharmacology and Department of Chemistry and Biochemistry, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0601, USA. 4. Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece. 5. Department of Pharmacology and Department of Chemistry and Biochemistry, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0601, USA. Electronic address: edennis@ucsd.edu. 6. Chemical Laboratories, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece. Electronic address: vikon@aua.gr.
Abstract
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.
Calcium-independent phospholipase A2 (GVIA n class="Gene">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.
Authors: David A Six; Efrosini Barbayianni; Vassilios Loukas; Violetta Constantinou-Kokotou; Dimitra Hadjipavlou-Litina; Daren Stephens; Alan C Wong; Victoria Magrioti; Panagiota Moutevelis-Minakakis; Sharon F Baker; Edward A Dennis; George Kokotos Journal: J Med Chem Date: 2007-08-02 Impact factor: 7.446
Authors: Varnavas D Mouchlis; Denis Bucher; J Andrew McCammon; Edward A Dennis Journal: Proc Natl Acad Sci U S A Date: 2015-01-26 Impact factor: 11.205
Authors: George Kokotos; Stavroula Kotsovolou; David A Six; Violetta Constantinou-Kokotou; Christopher C Beltzner; Edward A Dennis Journal: J Med Chem Date: 2002-07-04 Impact factor: 7.446
Authors: Tomader Ali; George Kokotos; Victoria Magrioti; Robert N Bone; James A Mobley; William Hancock; Sasanka Ramanadham Journal: PLoS One Date: 2013-08-20 Impact factor: 3.240