Synthetic Routes and Lipase-inhibiting Activity of Long-chain Alpha-keto Amides

Overview

Journal Lipids

Specialty Biochemistry

Date 2001 Jul 4

PMID 11432468

Citations 6

Authors

A Chiou

R Verger

G Kokotos

Affiliations

Soon will be listed here.

Abstract

Synthetic routes to primary and N-alkyl alpha-keto amides are presented in this paper. Primary alpha-keto amides may be prepared by using an aldehyde as starting material. Commercially available alpha-keto acids may be coupled in high yield with primary amines by the mixed carbonic anhydride method affording N-alkyl alpha-keto amides. Alternatively, N-alkyl alpha-keto amides may be prepared by coupling long-chain alpha-hydroxy acids with amino components, followed by oxidation with pyridinium dichromate or NaOCl in the presence of 4-acetamido-2,2,6,6-tetramethyl-1-piperidinyloxy free radical. The alpha-keto amide derivatives prepared according to these procedures were tested for their ability to form stable monomolecular films at the air/water interface. The inhibition of porcine pancreatic lipase by the alpha-keto amides, spread as mixed films with 1,2-dicaprin, was studied with the monolayer technique. Among the compounds tested in this study, methyl 2-[(2-ketododecanoyl)amino]hexadecanoate was shown to be the most potent inhibitor, causing a 50% decrease in lipase activity at a 0.09 molar fraction.

Citing Articles

Inhibitors of pancreatic lipase: state of the art and clinical perspectives.

Lunagariya N, Patel N, Jagtap S, Bhutani K EXCLI J. 2015; 13:897-921.

PMID: 26417311 PMC: 4464291.

Selenium dioxide-mediated synthesis of α-ketoamides from arylglyoxals and secondary amines.

Shaw A, Denning C, Hulme C Tetrahedron Lett. 2012; 53(32):4151-4153.

PMID: 23180891 PMC: 3501738. DOI: 10.1016/j.tetlet.2012.05.136.

Convergent synthesis of alpha-ketoamide inhibitors of Pin1.

Xu G, Etzkorn F Org Lett. 2010; 12(4):696-9.

PMID: 20102178 PMC: 2844255. DOI: 10.1021/ol9027013.

Structure-activity relationships of natural and non-natural amino acid-based amide and 2-oxoamide inhibitors of human phospholipase A(2) enzymes.

Antonopoulou G, Barbayianni E, Magrioti V, Cotton N, Stephens D, Constantinou-Kokotou V Bioorg Med Chem. 2008; 16(24):10257-69.

PMID: 18993078 PMC: 2796434. DOI: 10.1016/j.bmc.2008.10.046.

A novel monoacylglycerol lipase inhibitor with analgesic and anti-inflammatory activity.

Magrioti V, Naxakis G, Hadjipavlou-Litina D, Makriyannis A, Kokotos G Bioorg Med Chem Lett. 2008; 18(20):5424-7.

PMID: 18819796 PMC: 3712614. DOI: 10.1016/j.bmcl.2008.09.039.

References

Gargouri Y, Ransac S, Verger R . Covalent inhibition of digestive lipases: an in vitro study. Biochim Biophys Acta. 1997; 1344(1):6-37. DOI: 10.1016/s0005-2760(97)81102-2. View

Verger R, DE HAAS G, Sarda L, Desnuelle . Purification from porcine pancreas of two molecular species with lipase activity. Biochim Biophys Acta. 1969; 188(2):272-82. DOI: 10.1016/0005-2795(69)90075-0. View

Imperiali B, Abeles R . Inhibition of serine proteases by peptidyl fluoromethyl ketones. Biochemistry. 1986; 25(13):3760-7. DOI: 10.1021/bi00361a005. View

Stadler P, Zandonella G, Haalck L, Spener F, Hermetter A, Paltauf F . Inhibition of microbial lipases with stereoisomeric triradylglycerol analog phosphonates. Biochim Biophys Acta. 1996; 1304(3):229-44. DOI: 10.1016/s0005-2760(96)00123-3. View

Street I, Lin H, Laliberte F, Ghomashchi F, Wang Z, Perrier H . Slow- and tight-binding inhibitors of the 85-kDa human phospholipase A2. Biochemistry. 1993; 32(23):5935-40. DOI: 10.1021/bi00074a003. View

Tsutsumi S, OKONOGI T, Shibahara S, Ohuchi S, Hatsushiba E, PATCHETT A . Synthesis and structure-activity relationships of peptidyl alpha-keto heterocycles as novel inhibitors of prolyl endopeptidase. J Med Chem. 1994; 37(21):3492-502. DOI: 10.1021/jm00047a007. View

Li Z, Patil G, Golubski Z, Hori H, Tehrani K, Foreman J . Peptide alpha-keto ester, alpha-keto amide, and alpha-keto acid inhibitors of calpains and other cysteine proteases. J Med Chem. 1993; 36(22):3472-80. DOI: 10.1021/jm00074a031. View

Li Z, Patil G, Chu D, Foreman J, Eveleth D, POWERS J . Novel peptidyl alpha-keto amide inhibitors of calpains and other cysteine proteases. J Med Chem. 1996; 39(20):4089-98. DOI: 10.1021/jm950541c. View

Finer N, James W, Kopelman P, Lean M, Williams G . One-year treatment of obesity: a randomized, double-blind, placebo-controlled, multicentre study of orlistat, a gastrointestinal lipase inhibitor. Int J Obes Relat Metab Disord. 2000; 24(3):306-13. DOI: 10.1038/sj.ijo.0801128. View

10.

Ransac S, Gargouri Y, Marguet F, Buono G, Beglinger C, Hildebrand P . Covalent inactivation of lipases. Methods Enzymol. 1997; 286:190-231. DOI: 10.1016/s0076-6879(97)86012-0. View

11.

Cavalier J, Ransac S, Verger R, Buono G . Inhibition of human gastric and pancreatic lipases by chiral alkylphosphonates. A kinetic study with 1,2-didecanoyl-sn-glycerol monolayer. Chem Phys Lipids. 2000; 100(1-2):3-31. DOI: 10.1016/s0009-3084(99)00028-6. View

12.

Verger R . Interfacial enzyme kinetics of lipolysis. Annu Rev Biophys Bioeng. 1976; 5:77-117. DOI: 10.1146/annurev.bb.05.060176.000453. View

13.

Egloff M, Marguet F, Buono G, Verger R, Cambillau C, van Tilbeurgh H . The 2.46 A resolution structure of the pancreatic lipase-colipase complex inhibited by a C11 alkyl phosphonate. Biochemistry. 1995; 34(9):2751-62. DOI: 10.1021/bi00009a003. View

14.

Kokotos G, Martin V, Constantinou-Kokotou V, Gibbons W . Synthesis of medicinally useful lipidicα-amino acids, 2-amino alcohols and diamines. Amino Acids. 2013; 11(3-4):329-43. DOI: 10.1007/BF00807940. View

15.

Anderson G, Zimmerman J, Callahan F . A reinvestigation of the mixed carbonic anhydride method of peptide synthesis. J Am Chem Soc. 1967; 89(19):5012-7. DOI: 10.1021/ja00995a032. View

16.

Chiou A, Markidis T, Constantinou-Kokotou V, Verger R, Kokotos G . Synthesis and study of a lipophilic alpha-keto amide inhibitor of pancreatic lipase. Org Lett. 2000; 2(3):347-50. DOI: 10.1021/ol991295s. View

17.

Mannesse M, Boots J, Dijkman R, Slotboom A, van der Hijden H, Egmond M . Phosphonate analogues of triacylglycerols are potent inhibitors of lipase. Biochim Biophys Acta. 1995; 1259(1):56-64. DOI: 10.1016/0005-2760(95)00145-3. View

18.

Ackermann E, Dennis E . Inhibition of macrophage Ca(2+)-independent phospholipase A2 by bromoenol lactone and trifluoromethyl ketones. J Biol Chem. 1995; 270(1):445-50. DOI: 10.1074/jbc.270.1.445. View

19.

Bjorkling F, Dahl A, Patkar S, Zundel M . Inhibition of lipases by phosphonates. Bioorg Med Chem. 1994; 2(7):697-705. DOI: 10.1016/0968-0896(94)85020-8. View

20.

Verger R, DE HAAS G . Enzyme reactions in a membrane model. 1. A new technique to study enzyme reactions in monolayers. Chem Phys Lipids. 1973; 10(2):127-36. DOI: 10.1016/0009-3084(73)90009-1. View