130633-92-0Relevant academic research and scientific papers
Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by β-glucuronidase
Rawale, Sharad,Hrihorczuk, Lew M.,Wei, Wei-Zen,Zemlicka, Jiri
, p. 937 - 943 (2007/10/03)
The first synthesis of a prodrug of HLA-A2.1 associated antigenic influenza peptide 2a was accomplished. Two methods for synthesis of prodrugs of antigenic peptides activated by β-glucuronidase and comprising a self-immolative 3-nitrobenzyloxycarbonyl moiety were investigated. Reaction of β-glucuronic acid glycoside of 4-hydroxy-3-nitrobenzyl alcohol (3) with N,N′-disuccinimidyl carbonate (DSC) followed by conjugation with AlaOMe, Gly, Thr, Phe-Leu, and Leu-Arg gave carbamates 4a-4f. Deacetylation of 4b and 4e with MeONa/MeOH gave β-glucuronides 5b and 5e. Compound 5e was converted to β-glucuronic acid conjugate 6e by the action of pig liver esterase (PLE). Compound 6e is a substrate for β-glucuronidase. Method of a direct introduction of the prodrug residue into antigenic nonapeptide GILGFVFTL (2b) failed. Alternately, glycine conjugate 5b was activated to pentafluorophenyl ester 10. Model coupling of 10 with Phe-Leu gave tripeptide conjugate ester 11a which was hydrolyzed by PLE to uronic acid 12. Condensation of 10 with octapeptide ILGFVFTL (9) gave prodrug precursor 11b. Octapeptide 9 was prepared by de novo synthesis using a racemization-free fragment coupling method. Ester hydrolysis with Ba(OH)2/MeOH gave the target prodrug 2a which is a substrate for β-glucuronidase. Prodrug 2a does not bind to HLA-A2.1 of T2 human cells defective in major histocompatibility complex I (MHC I)-associated peptide processing. Addition of β-glucuronidase restored the binding to the level observed with parent nonapeptide 2b although higher concentrations of prodrug 2a and enzyme were necessary.
