Τίτλος:
β-Lactones: A Novel Class of Ca 2+ -Independent Phospholipase A 2 (Group VIA iPLA 2 ) Inhibitors with the Ability To Inhibit β-Cell Apoptosis
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Ca 2+ -independent phospholipase A 2 (GVIA iPLA 2 ) has gained increasing interest recently as it has been recognized as a participant in biological processes underlying diabetes development and autoimmune-based neurological disorders. The development of potent GVIA iPLA 2 inhibitors is of great importance because only a few have been reported so far. We present a novel class of GVIA iPLA 2 inhibitors based on the β-lactone ring. This functionality in combination with a four-carbon chain carrying a phenyl group at position-3 and a linear propyl group at position-4 of the lactone ring confers excellent potency. trans-3-(4-Phenylbutyl)-4-propyloxetan-2-one (GK563) was identified as being the most potent GVIA iPLA 2 inhibitor ever reported (X I (50) 0.0000021, IC 50 1 nM) and also one that is 22 000 times more active against GVIA iPLA 2 than GIVA cPLA 2 . It was found to reduce β-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes. © 2019 American Chemical Society.
Συγγραφείς:
Dedaki, C.
Kokotou, M.G.
Mouchlis, V.D.
Limnios, D.
Lei, X.
Mu, C.T.
Ramanadham, S.
Magrioti, V.
Dennis, E.A.
Kokotos, G.
Περιοδικό:
Journal of Medicinal Chemistry
Εκδότης:
American Chemical Society
Λέξεις-κλειδιά:
2 (1 hydroxyethyl) 5 (naphthalen 2 yl)pentanoic acid; 2 [3 [(1,1 biphenyl) 4 yl]propyl] 3 hydroxynonanoic acid; 3 (3 phenylpropyl) 4 propyloxetan 2 one; 3 (4 phenylbutyl) 4 propyloxetan 2 one; 3 hydroxy 2 (3 phenylpropyl)hexanoic acid; 3 hydroxy 2 (3 phenylpropyl)nonanoic acid; 3 hydroxy 2 (4 phenylbutyl)hexanoic acid; 3 hydroxy 2 [3 (4 methoxyphenyl)propyl]hexanoic acid; 3 hydroxy 2 [3 (naphthalen 2 yl)propyl]hexanoic acid; 3 hydroxy 2 [3 (naphthalen 2 yl)propyl]nonanoic acid; 3 hydroxy 2 [3 (naphthalen 2 yl)propyl]pentanoic acid; 3 hydroxy 2 [4 (naphthalen 2 yl)butyl]hexanoic acid; 3 hydroxy 4 methyl 2 (3 phenylpropyl)pentanoic acid; 3 [3 (4 methoxyphenyl)propyl] 4 propyloxetan 2 one; 3 [3 (naphthalen 2 yl)propyl] 4 propyloxetan 2 one; 3 [3 [(1,1' biphenyl) 4 yl]propyl] 4 hexyloxetan 2 one; 3 [4 (naphthalen 2 yl)butyl] 4 propyloxetan 2 one; 4 ethyl 3 [3 (naphthalen 2 yl)propyl]oxetan 2 one; 4 hexyl 3 (3 phenylpropyl)oxetan 2 one; 4 hexyl 3 [3 (naphthalen 2 yl)propyl]oxetan 2 one; 4 isopropyl 3 (3 phenylpropyl)oxetan 2 one; 4 methyl 3 [3 (naphthalen 2 yl)propyl]oxetan 2 one; antidiabetic agent; calcium independent phospholipase A2; carbon; gk 563; phenyl group; phospholipase A2; phospholipase A2 inhibitor; propane; unclassified drug; autacoid; calcium independent phospholipase A2; cytokine; lactone; phospholipase A2 inhibitor, antidiabetic activity; apoptosis; Article; concentration response; controlled study; diastereoisomer; drug binding; drug design; drug potency; drug selectivity; drug synthesis; enzyme inhibition; human; human cell; IC50; in vitro study; nonhuman; pancreas islet beta cell; animal; apoptosis; chemistry; drug effect; metabolism; pancreas islet beta cell; physiology; structure activity relation, Animals; Apoptosis; Cytokines; Drug Design; Humans; Inflammation Mediators; Insulin-Secreting Cells; Lactones; Phospholipase A2 Inhibitors; Phospholipases A2, Calcium-Independent; Structure-Activity Relationship
DOI:
10.1021/acs.jmedchem.8b01216
