Bis-2-oxo Amide Triacylglycerol Analogues:  A Novel Class of Potent Human Gastric Lipase Inhibitors

Abstract

A novel class of potent human gastric lipase inhibitors, bis-2-oxo amide triacylglycerol analogues, was developed. These analogues of the natural substrate of lipases were prepared starting from 1,3-diaminopropan-2-ol. They were designed to contain the 2-oxo amide functionality in place of the scissile ester bond at the sn-1 and sn-3 position, while the ester bond at the sn-2 position was either maintained or replaced by an ether bond. The derivatives synthesized 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 bis-2-oxo amides was studied using the monolayer technique with mixed films of 1,2-dicaprin containing variable proportions of each inhibitor. The nature of the functional group (ester or ether), as well as the chain length, at the sn-2 position influenced the potency of the inhibition. Among the compounds tested, 2-[(2-oxohexadecanoyl)amino]-1-[[(2-oxohexadecanoyl)-amino]methyl]ethyl decanoate was the most potent inhibitor, causing a 50% decrease in HPL and HGL activities at 0.076 and 0.020 surface molar fractions, respectively.

Novel Trifluoromethyl Ketones as Potent Gastric Lipase Inhibitors

“…On the contrary, HGL showed a strong preference (sevenfold) for the ester derivatives ( 9 b and ( R )‐ 9 b ) as compared to the ether derivative ( 9 a ). The observation that a carboxy ester bond involving the secondary hydroxy group (corresponding to the sn ‐2 position of the natural TAG substrates) is important for the inhibition of HGL is in agreement with previous findings on bis‐2‐oxo amide triacylglycerol analogue inhibitors 7b. The results obtained with compounds 9 b and ( R )‐ 9 b showed that the chirality did not affect their inhibitory effect on either HPL or HGL.…”

A High Salt-Tolerant Thermoactive Esterase from Golden Grey Mullet: Purification, Characterization and Kinetic Properties

“…; Kotsovolou et al . ). In this study, the enzyme was incubated with various metal ions (at 10 mM) and activities were recorded within 30 min.…”

“…Understanding the role of lipase effectors may provide a better evaluation of their mechanism of action (Bray 2000) and result in their application in certain treatments (Sztajer et al 1992;Kotsovolou et al 2001). In this study, the enzyme was incubated with various metal ions (at 10 mM) and activities were recorded within 30 min.…”

Synthesis and activity of 2-oxoamides containing long chain β-amino acids

“…The 2-oxoamide functionality has been used successfully in the development of inhibitors of various lipolytic enzymes, which are characterized as serine hydrolases. It has been demonstrated that lipophilic 2-oxoamides [6,7], 2-oxoamide and bis-2oxoamide triacylglycerol analogues [8,9] are efficient inhibitors of pancreatic and gastric lipases, enzymes containing a classic catalytic triad (Ser-His-Asp).…”