Design and synthesis of Fmoc-Thr[PO(OH)(OPOM)] for the preparation of peptide prodrugs containing phosphothreonine in fully protected form.
The design and efficient synthesis of N-Fmoc-phosphothreonine protected by a mono-(pivaloyloxy)methyl (POM) moiety at its phosphoryl group (Fmoc-Thr[PO(OH)(OPOM)]-OH, 1, is reported. This reagent is suitable for solid-phase syntheses employing acid-labile resins and Fmoc-based protocols. It allows the preparation of phosphothreonine (pThr)-containing peptides bearing bis-POM-phosphoryl protection. The methodology allows the first reported synthesis of pThr-containing polypeptides having bioreversible prodrug protection, and as such it should be useful in a variety of biological applications.
Chemical Biology Laboratory, Molecular Discovery Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, P.O. Box B, Frederick, MD 21702, USA, (phone: +1-301-8465906; fax: +1-301-8466033).
Wen-Jian
WJ
Qian
Christopher C
CC
Lai
James A
JA
Kelley
Terrence R
TR
Burke
D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry*; D015195:Drug Design; D005449:Fluorenes / Q000138:chemical synthesis / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D010769:Phosphothreonine / Q000138:chemical synthesis / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry*
D000596:Amino Acids; D005449:Fluorenes; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D010455:Peptides; D011355:Prodrugs; D010769:Phosphothreonine
Peptides; Phosphothreonine; Prodrug; Signal transduction; Solid-phase synthesis