Gilles Sauve

Chemoselective thioacylation of amino acids. Preparation of the four monothiothymopentin analogs and their biological activity

Abstract A methodology for the specific site incorporation of thioamide linkages into a growing peptide under mild conditions using thioacylating agent 1 is described. Thus, the synthesis of the four monothioanalogues of thymopentin (TP-5): [Valt4]- 18, [Aspt3]- 19, [Lyst2]- 20 and [Argt1]- 17 is reported. These thiopeptides retained the biological activity of the parent compound.

Some remarkable effects of thiopeptide and derived linkages on lysozyme release from neutrophils by esters of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (f-Met-Leu-Phe-OR)

A variety of recently synthesized analogues of the chemotactic agent f-Met-Leu-Phe-OR modified in the backbone were tested for their ability to induce the release of lysozyme from human neutrophils. In sharp contrast to the effects of thiopeptide linkages on the biological activity of Leu5-enkephalin as previously reported, the presence of single thioamide bonds at either one of the endo-positions of the chemotactic peptide, abolished activity. Thioamide-derived linkages such as amidoximes and cyanamidines were generally also detrimental to activity, except in the cases of the cyanamidoformyl derivatives which showed enhanced activity and two amidoxime esters, one O-acetylated and the other O-esterified intramolecularly, which retained moderate activity. The mechanistic significance of these results is discussed in terms of conformational effects on receptor recognition.

Carboxyl-modified amino acids and peptides. I: An efficient method for the synthesis of monofunctionalized enamines and monofunctionalized methyl ketone derivatives from thioamides via episulfides and thioiminium salts

Abstract Thioamides 4 were transformed by two convenient routes to various functionalized enamines 7 containing different electron-withdrawing groups E which on subsequent hydrolysis gave the corresponding methyl ketone derivatives 8 . Application of this methodology to obtain modified dipeptides at the carboxyl end, the determination of stereochemistry and the degree of racemization are discussed.

1,2,5,6-Tetra-O-benzyl-d-mannitol derivatives as novel HIV protease inhibitors

The synthesis and structure-activity relationships of HIV protease inhibitors derived from carbohydrate alditols are discussed. We disclose a new series of 1,2,5,6-tetra-O-alkyl-D-mannitol exhibiting sub-micromolar activity against HIV-protease. This series of inhibitors are non-nitrogen containing HIV-protease inhibitors and they are readily prepared in a few chemical steps from inexpensive commercially available starting materials.

Carboxyl-modified amino acids and peptides: II) A convenient route for the synthesis of difunctionalized enamines from thioamides via thioiminium salts

Abstract From thioamides 4, via thioiminium salts 5, various difunctionalized enamines 6 with different electron-withdrawing groups E, E′ (E: CN, CO2Me, COR, SO2R, etc; E′: CN, CO2Me) are prepared. Application of the methodology, the determination of stereochemistry and the degree of racemization of some amino acids are discussed.