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

Anneta Smyrniotou; Maroula G Kokotou; Varnavas D Mouchlis; Efrosini Barbayianni; George Kokotos; Edward A Dennis; Violetta Constantinou-Kokotou

doi:10.1016/j.bmc.2016.12.007

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

Bioorg Med Chem. 2017 Feb 1;25(3):926-940. doi: 10.1016/j.bmc.2016.12.007. Epub 2016 Dec 8.

Authors

Anneta Smyrniotou¹, Maroula G Kokotou², Varnavas D Mouchlis³, Efrosini Barbayianni⁴, George Kokotos⁴, Edward A Dennis⁵, Violetta Constantinou-Kokotou⁶

Affiliations

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 (X_I(50) value of 0.007) and at the same time significant selectivity over GIVA cPLA₂ and GV sPLA₂.

Keywords: Dipeptides; Inhibitors; Oxoamides; Phospholipase A(2); Pseudodipeptides.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Dipeptides / chemical synthesis
Dipeptides / chemistry
Dipeptides / pharmacology*
Dose-Response Relationship, Drug
Humans
Molecular Structure
Phospholipase A2 Inhibitors / chemical synthesis
Phospholipase A2 Inhibitors / chemistry
Phospholipase A2 Inhibitors / pharmacology*
Phospholipases A2, Calcium-Independent / antagonists & inhibitors*
Phospholipases A2, Calcium-Independent / metabolism
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Dipeptides
Phospholipase A2 Inhibitors
Pyridines
oxoamide
Phospholipases A2, Calcium-Independent

Grants and funding

R01 GM020501/GM/NIGMS NIH HHS/United States