228412-63-3

Upstream product

• 148579-94-6 (25,3R,45,55,65)-2-(4-(hydroxymethyl)-2-nitrophenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 
• 56-40-6 glycine 
• 148580-01-2 (2S,3S,4S,5R,6S)-3,4,5-Triacetoxy-6-[2-nitro-4-(4-nitro-phenoxycarbonyloxymethyl)-phenoxy]-tetrahydro-pyran-2-carboxylic acid methyl ester 

Downstream Products

• 228412-67-7 5-fluoro-N-<4-O--3-nitrobenzyloxycarbonyl>-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethylamine 
• 228412-68-8 5-fluoro-N-<4-O--3-nitrobenzyloxycarbonyl>-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethylamine 
• 403852-44-8 methyl N-[β-D-glucopyranuronate-3-nitrobenzyloxycarbonyl]-Gly-Ile-Leu-Gly-Phe-Val-Phe-Thr-Leu-OH 
• 403852-50-6 N-[β-D-(glucopyranuronic acid)-3-nitrobenzyloxycarbonyl]-Gly-Ile-Leu-Gly-Phe-Val-Phe-Thr-Leu-OH 
• 403852-43-7 methyl N-[β-D-glucopyranuronate-3-nitrobenzyloxycarbonyl]glycyl-L-phenylalanyl-L-leucine 
• 404002-11-5 methyl N-[β-D-glucopyranuronate-3-nitrobenzyloxycarbonyl]glycine pentafluorophenyl ester 
• 403852-39-1 methyl N-[β-D-glucopyranuronate-3-nitrobenzyloxycarbonyl]glycine 
• 228412-65-5 N-<4-O--3-nitrobenzyloxycarbonyl>acetoxymethylamine 

Relevant academic research and scientific papers

Synthesis and biological activity of the prodrug of class I major histocompatibility peptide GILGFVFTL activated by β-glucuronidase

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.

Synthesis of self-immolative glucuroenide spacers based on aminomethylcarbamate. Application to 5-fluorouracil prodrugs for antibody-directed enzyme prodrug therapy

The synthesis of three novel potential glucuronide-based prodrugs for antibody-directed enzyme prodrug therapy (ADEPT) is described. These prodrugs were designed to be activated at the tumour site by -glucuronidase to afford the corrresponding anticancer agent, 5-FU. The structural pattern of these compounds includes a self-immolative spacer between the glucuronyl residue and the N1 of 5-FU. Three types of spacers have been elaborated which, after enzymic hydrolysis, spontaneously decompose to deliver an unstable N1 aminal 5-FU derivative and, from there, the cytotoxic drug. All potential prodrugs were stable and proved to be excellent substrates of E. coll in in vitro experiments.