Sterically Hindered Triacylglycerol Analogues as Potent Inhibitors of Human Digestive Lipases

Abstract

A novel class of inhibitors of human digestive lipases have been developed. Various sterically hindered triacylglycerols based on 2-methyl- and 2-butylglycerol, and/or 2-methyl fatty acids were synthesized. The triacylglycerol analogues 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 human pancreatic and gastric lipases by the sterically hindered triacylglycerol analogues was studied by using the monolayer technique with mixed films of 1,2-dicaprin, which contained variable proportions of each inhibitor. Triolein analogues that contain a butyl group at the 2-position of the glycerol backbone or methyl groups both at the 2-position of glycerol, and the alpha-position of each oleic acid residue were potent inhibitors; this caused a 50% decrease in HPL activity at 0.003 molar fraction.

Interactions of fatty acids with phosphatidylethanolamine membranes: X-ray diffraction and molecular dynamics studies

“…2-hydroxystearic acid (2OHSA) was purchased from Larodan (Malmö, Sweden), and 1,2-dielaidoyl -sn-glycero-3-phosphoethanolamine (DEPE) and 2-hydroxyoleic acid (2OHOA) were purchased from Avanti Polar Lipids, Inc. (Alabaster, AL). 2-methyloleic acid was synthesized as described elsewhere ( 20 ) with a purity of 90%. Lipids were stored under argon at Ϫ 80°C.…”

Development of a Multikilogram Synthesis of a Chiral Epoxide Precursor to a CCR1 Antagonist. Use of in Situ Monitoring for Informed Optimisation via Fragile Intermediates

“…The dihydroxylation of 2-methyl-2-propen-1-ol ( 6 ) was achieved by treatment with H 2 O 2 in water, in the presence of a catalytic amount of Na 2 WO 4 . 2-Methylglycerol ( 15 ) was treated with acetone in the presence of catalytic p -toluenesulfonic acid to afford ( R , S )-2,2,4-trimethyl-1,3-dioxolane-4-methanol ( 16 ) . Racemate 16 was subsequently esterified using succinic anhydride in TBME, and an enzymatic resolution was subsequently achieved via hydrolysis catalysed by Pseudomonas cepacia lipase on Celite (Amano PS-D) giving 12 and the undesired ( R )-succinate half ester ( 17 ) which was removed by extraction into the aqueous phase.…”

Chitosan does not inhibit enzymatic action of human pancreatic lipase in Langmuir monolayers of 1,2-didecanoyl-glycerol (DDG)

“…Porcine pancreatic lipase had its enzymatic activity inhibited in olive oil emulsions containing galactolipid digalactosyldiacylglycerol (DGDG) [28], while a mixed monolayer of DGDG/bile salts hampered porcine pancreatic lipase/colipase adsorption to the interface by steric hindrance of galactosyl groups [29]. Triacylglycerols have been also found to inhibit lipases [30].…”