Thioamides:  Synthesis, Stability, and Immunological Activities of Thioanalogues of Imreg. Preparation of New Thioacylating Agents Using Fluorobenzimidazolone Derivatives

Abstract

Imreg (Tyr-Gly-Gly) is a well-known immunostimulant. However, it possesses a short half-life. Stabilized analogues of Imreg were prepared by a regioselective insertion in which peptide bonds at position 1,2 or 2,3 were replaced by thioamide linkages. This was achieved by using new thioacylating agents based on thioacyl-fluoro-N-benzimidazolone. The synthesis and properties of these reagents are described herein. This peptide modification enhanced significantly the half-life of the thioanalogues relative to Imreg in blood. The thioanalogues and Imreg were tested in vitro in T and B cell proliferation assays and for their ability to stimulate cytotoxic T-lymphocytes (CTLs). Only thiotyrosyl glycyl glycine 11 displayed some activity as evidenced by a weak stimulation of CTLs. On the basis of this activity and the increased stability, an in vivo immunological evaluation was undertaken. Immunophenotyping of 11 revealed a significant increase in activated CTL and NK cell populations in the spleen. This expansion was also accompanied by a significant stimulation of NK cells and the B cell proliferative response. Thioanalogues of Imreg were generally nontoxic, as exemplified by 11. The latter is a promising immunostimulant which may be targeted for cancer and viral infections, where CTLs and NK cells play an important role, or as a vaccine adjuvant where stimulation of antibody-producing B cells is important.

Coupling‐Reagent‐Free Synthesis of Dipeptides and Tripeptides Using Amino Acid Ionic Liquids

“…Then, tyrosyl‐glycyl‐glycine ( 6 b ), present in IMREG‐1 and possessing immune stimulation properties,10 was chosen as a model tripeptide. 6 b has previously been prepared by a traditional protection/deprotection sequence from N ‐Boc‐protected tyrosine and glycyl‐glycine benzyl ester using 2‐ethoxy‐1‐ethoxycarbonyl‐1,2‐dihydroquinoline as a coupling reagent 10a. Tyrosine methyl ester HCl salt ( 1 e ) reacted with 3 c (5.4 equiv) smoothly at 60 °C to give tyrosyl‐glycyl‐glycine ( 6 b ) (Scheme , bottom).…”

Thiosemicarbazones as Aedes aegypti larvicidal

“…H-bond) with a biological target owing to the chemical change C=O for C=S in the above-mentioned compound. Another plausible hypothesis for explaining this change in the larvicide activity may be related to the higher M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT stability of the thiopeptidic compared to the peptidic environment under attack by proteolytic enzymes [74].…”

The Application of Microwaves in Combinatorial and High‐Throughput Synthesis as New Synthetic Procedure in Drug Discovery

“…Parallel Synthesis of Thioamides: One approach to increase the half-life of peptides is to substitute one or more amide linkages by thioamide linkages, a modification leading to improved resistance to enzyme degradation [67]. Olsson et al [68] described a simple solvent-free synthesis of thioamides treating a library of amides, obtained by mixing acyl chlorides 118 and diamines 119 with Lawessons reagent.…”