Michel Level

A comparative 1H-N.M.R. study of MurNAc-l-Ala-d-iGln (MDP) and its analogue murabutide: Evidence for a structure involving two successive β-turns in MDP

The active principle, MurNAc-L-Ala-D-iGln (MDP), of complete Freunds adjuvant and its analogue, MurNAc-L-Ala-D-Gln-OnBu (murabutide), which express immunomodulatory as well as other biological properties, have been studied by 2D-1H-n.m.r. spectroscopy at 500 MHz. The results suggest the presence in MDP of two successive turns involving the MurNAc-L-Ala and L-Ala-D-iGln moieties, respectively, whereas only the former turn persists in murabutide. This turn mimics the type II beta-turn found in L-D depsipeptides, whereas the other is a typical type II beta-turn for L-D peptides.

Selectively O-acylated glycosaminoglycan derivatives

Abstract Glycosaminoglycans, particularly heparin and heparin fragments, were specifically O -acetylated by use of tetrabutylammonium or tributylammonium salts of the anionic polysaccharides, carboxylic acid anhydrides, and 4-dimethylaminopyridine in an homogeneous way in N,N -dimethylformamide. The number of acyl chains introduced on the carbohydrate backbone was determined either after transesterification and quantitative analysis of the butyl esters thus obtained by GLC or by 1 H NMR spectroscopy.

Synthesis of phosphono analogues of 3-deoxy -d-arabino-hept-2-ulosonic acid 7-phosphate☆

Abstract 3,7,8-Trideoxy-8-phosphono- d - arabino -octulosonic acid and 7,8-dedeoxy-8-phosphobno-D- gluco -octulosonic acid were synthesised in six step from known, protected derivatives of 2-deoxy- d - arabino -hexose and d -glucose. The protected 6- aldehydo -hexadialdoses were condensed with tetraethyl methylenediphosphonate, and hydrolysis of vinylphosphonate was effected indirectly by transesterification with bromotrimethylsilane. Cyanide addition to deprotected heptose phosphonates was followed by chlorate-vanadate oxidation to octulosonic acid derivatives. The corresponding 3,7-dideoxy-7-phosphono- d - arabino -heptulosonic acid and 7-deoxy-7-phosphono- d - gluco -heptulosonic acid were obtained by reaction of 6-bromo-6-deoxyhexoses with triethyl phosphite, followed by treatment with bromotrimethylsilane, hydrolysis with water, cyanide homologation, and chlorate-vanadate oxidation. All four, final phosphono compounds are competitive inhibitors of 3-dehydroquinate syntyhetase.

O-Acylated heparin derivatives with low anticoagulant activity decrease proliferation and increase α-smooth muscle actin expression in cultured arterial smooth muscle cells

Selectively O-acylated derivatives of various glycosaminoglycans were prepared and tested in vitro for their anticoagulant activity and their antiproliferative effect on rat and rabbit smooth muscle cells. When O-acylation (butyrylation or hexanoylation) had been performed on periodate-depolymerized heparin fragments having very low anticoagulant activity, the antiproliferative potency was markedly increased (IC50 = 2 and 1 micrograms/ml respectively, versus 31 micrograms/ml for starting compound) without an increase in anticoagulant activity. The antiproliferative activity was related to the degree of acylation. The O-acylated derivatives of heparin fragments were also very active in reversing the de-differentiation of smooth muscle cell in culture, as estimated by the increase in the expression of alpha-smooth muscle actin and alpha-smooth muscle actin mRNA.

The interaction of phosphonate and homophosphonate analogues of 3-deoxy-D-arabino heptulosonate 7-phosphate with 3-dehydroquinate synthetase from Escherichia coli

Abstract Phosphonate and homophosphonate analogues of 3-deoxy-D- arabino heptulosonate 7-phosphate and D- gluco heptulosonate 7-phosphate behave as competitive inhibitors of 3-dehydroquinate synthetase. Phosphonates have better affinities than homophosphonates and protect efficiently the enzyme against thermal denaturation. No evidence has been obtained for 5-keto phosphonate intermediate formation in the interaction of such analogues with 3-dehydroquinate synthetase and NAD+.

Enzymic properties of phosphonic analogues of D-erythrose 4-phosphate

Abstract 4-Deoxy-D- erythro tetrose 4-phosphonate and 4,5 dideoxy D- erythro pentose 5-phosphonate, the phosphonic analogues of D-erythrose 4-phosphate, have been prepared by oxidation of the corresponding analogues of glucose 6-phosphate and tested as substrates of 3-deoxy-D- arabino heptulosonate 7-phosphate synthetase, transaldolase and transketolase. Kinetic parameters of the reaction with the phosphonate analogues and the natural substrate have been compared.