Antonopoulou G, Barbayianni E, Magrioti V, Cotton N, Stephens D, Constantinou-Kokotou V, Dennis EA, Kokotos G.
Structure-activity relationships of natural and non-natural amino acid-based amide and 2-oxoamide inhibitors of human phospholipase A2 enzymes. Bioorganic and Medicinal Chemistry. 2008;16(24):10257-10269.
AbstractA variety of 2-oxoamides and related amides based on natural and non-natural amino acids were synthesized. Their activity on two human intracellular phospholipases (GIVA cPLA2 and GVIA iPLA2) and one human secretory phospholipase (GV sPLA2) was evaluated. We show that an amide based on (R)-γ-norleucine is a highly selective inhibitor of GV sPLA2.
Antonopoulou G, Magrioti V, Stephens D, Constantinou-Kokotou V, Dennis EA, Kokotos G.
Synthesis of 2-oxoamides based on sulfonamide analogs of gamma-amino acids and their activity on phospholipase A2. Journal of Peptide Science. 2008;14(10):1111-1120.
AbstractA variety of lipophilic 2-oxoamides containing sulfonamide analogs of γ-amino acids as well as acyl sulfonamides of γ-aminobutyric acid were synthesized. Their ability to inhibit intracellular GIVA cPLA2 and GVIA iPLA2 as well as secreted GV sPLA2 was evaluated. The sulfonamide group seems a bioisosteric group suitable to replace the carboxyl group in 2-oxoamide inhibitors of GVIA cPLA2.
Baskakis C, Magrioti V, Cotton N, Stephens D, Constantinou-Kokotou V, Dennis EA, Kokotos G.
Synthesis of polyfluoro ketones for selective inhibition of human phospholipase A2 enzymes. Journal of Medicinal Chemistry. 2008;51(24):8027-8037.
AbstractThe development of selective inhibitors for individual PLA2 enzymes is necessary in order to target PLA2-specific signaling pathways, but it is challenging due to the observed promiscuity of known PLA2 inhibitors. In the current work, we present the development and application of a variety of synthetic routes to produce pentafluoro, tetrafluoro, and trifluoro derivatives of activated carbonyl groups in order to screen for selective inhibitors and characterize the chemical properties that can lead to selective inhibition. Our results demonstrate that the pentafluoroethyl ketone functionality favors selective inhibition of the GVIA iPLA2, a very important enzyme for which specific, potent, reversible inhibitors are needed. We find that 1,1,1,2,2-pentafluoro-7-phenyl-heptan-3-one (FKGK11) is a selective inhibitor of GVIA iPLA2 (XI(50) = 0.0073). Furthermore, we conclude that the introduction of an additional fluorine atom at the α′ position of a trifluoromethyl ketone constitutes an important strategy for the development of new potent GVIA iPLA2 inhibitors.
Magrioti V, Naxakis G, Hadjipavlou-Litina D, Makriyannis A, Kokotos G.
A novel monoacylglycerol lipase inhibitor with analgesic and anti-inflammatory activity. Bioorganic and Medicinal Chemistry Letters. 2008;18(20):5424-5427.
AbstractA variety of long chain 1,2-diamines and related compounds were synthesized and tested for their activity on fatty acid amide hydrolase (FAAH) and monoacyglycerol lipase (MGL). (2S,9Z)-Octadec-9-ene-1,2-diamine selectively inhibits MGL (Ki 21.8 μM) without significantly affecting FAAH. This compound exhibited interesting in vivo analgesic and anti-inflammatory properties, suggesting that selective inhibitors of MGL may be valuable novel agents for the treatment of inflammatory pain.
