Synthesis of 2-Oxo amide triacylglycerol analogues and study of their inhibition effect on pancreatic and gastric lipases.
A general method for the synthesis of chiral 2-oxo amide triacylglycerol analogues, from (R)- or (S)-3-aminopropane-1,2-diol, was developed. These novel inhibitors of digestive lipases are analogues of the triacylglycerol molecule, a natural substrate of lipases, and they were designed to contain the 2-oxo amide functionality in place of the scissile ester bond at the sn-1 or sn-3 position and nonhydrolysable ether bonds instead of ester bonds at the other two remaining positions. The 2-oxo amide derivatives synthesised were tested for their ability to form stable monomolecular films at the air/water interface by recording their surface pressure/molecular area compression isotherms. The inhibition of porcine pancreatic and human gastric lipases by the 2-oxo amides was studied by means of the monolayer technique with mixed films of 1,2-dicaprin and with variable proportions of each inhibitor. The alpha50 values of these triacylglycerol analogues for PPL and HGL varied between 4.4 to 7.0% and 5.6 to 15.9%, respectively. The chirality at the sn-2 position of 2-oxo amide triacylglycerol analogues affected the alpha50 value for HGL, but not for PPL.
Kokotos
G
G
Department of Chemistry, University of Athens, Greece. gkokotos@cc.uoa.gr
Verger
R
R
Chiou
A
A
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008049:Lipase / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D010179:Pancreas / Q000201:enzymology*; D013270:Stomach / Q000201:enzymology*; D014280:Triglycerides / Q000138:chemical synthesis* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014280:Triglycerides; D008049:Lipase