Document Detail

Design and synthesis of phosphotyrosine peptidomimetic prodrugs.
MedLine Citation:
PMID:  16722656     Owner:  NLM     Status:  MEDLINE    
A novel approach to the intracellular delivery of aryl phosphates has been developed that utilizes a phosphoramidate-based prodrug approach. The prodrugs contain an ester group that undergoes reductive activation intracellularly with concomitant expulsion of a phosphoramidate anion. This anion undergoes intramolecular cyclization and hydrolysis to generate aryl phosphate exclusively with a t(1/2) = approximately 20 min. Phosphoramidate prodrugs (8-10) of phosphate-containing peptidomimetics that target the SH2 domain were synthesized. Evaluation of these peptidomimetic prodrugs in a growth inhibition assay and in a cell-based transcriptional assay demonstrated that the prodrugs had IC50 values in the low micromolar range. Synthesis of phosphorodiamidate analogues containing a P-NH-Ar linker (16-18) was also carried out in the hope that the phosphoramidates released might be phosphatase-resistant. Comparable activation rates and cell-based activities were observed for these prodrugs, but the intermediate phosphoramidate dianion underwent spontaneous hydrolysis with a t(1/2) = approximately 30 min.
Hugo Garrido-Hernandez; Kyung D Moon; Robert L Geahlen; Richard F Borch
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  49     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2006 Jun 
Date Detail:
Created Date:  2006-05-25     Completed Date:  2006-07-12     Revised Date:  2013-06-07    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3368-76     Citation Subset:  IM    
Department of Medicinal Chemistry and Molecular Pharmacology, and the Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
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MeSH Terms
Amides / chemical synthesis,  pharmacology
Cell Membrane Permeability
Cell Proliferation / drug effects
Drug Design
Jurkat Cells
Molecular Mimicry
Organophosphates / chemical synthesis*,  chemistry,  pharmacology
Peptides / chemistry*
Phosphoric Acids / chemical synthesis,  pharmacology
Phosphotyrosine / analogs & derivatives*,  chemical synthesis*,  chemistry,  pharmacology
Prodrugs / chemical synthesis*,  chemistry,  pharmacology
Structure-Activity Relationship
src Homology Domains
Grant Support
P30 CA23168/CA/NCI NIH HHS; R01 CA034619-17/CA/NCI NIH HHS; R01 CA034619-18A1/CA/NCI NIH HHS; R01 CA034619-19/CA/NCI NIH HHS; R01 CA034619-20/CA/NCI NIH HHS; R01 CA34619/CA/NCI NIH HHS
Reg. No./Substance:
0/Amides; 0/Organophosphates; 0/Peptides; 0/Phosphoric Acids; 0/Prodrugs; 21820-51-9/Phosphotyrosine; 9Q189608GB/phosphoramidic acid

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