Document Detail

Synthesis and biological activity of aromatic amino acid phosphoramidates of 5-fluoro-2'-deoxyuridine and 1-beta-arabinofuranosylcytosine: evidence of phosphoramidase activity.
MedLine Citation:
PMID:  8917645     Owner:  NLM     Status:  MEDLINE    
The amino acid phosphoramidate diesters of FUdR (2) and Ara-C (6), 5-fluoro-2'-deoxy-5'-uridyl N-(1-carbomethoxy-2-phenylethyl)phosphoramidate (5a), 5-fluoro-2'-deoxy-5'- uridyl N-(1-carbomethoxy-2-indolylethyl)phosphoramidate (5b), 1-beta-arabinofuranosylcytosine 5'-N-(1-carbomethoxy-2-phenylethyl) phosphoramidate (8a), and 1-beta-arabinofuranosylcytosine 5'-N-(1-carbomethoxy-2-indolylethyl)phosphoramidate (8b), were synthesized and tested for their antitumor activity against L1210 mouse lymphocytic leukemia cells and CCRF-CEM human T-cell lymphoblastic leukemia cells. Ara-C phosphoramidates 8a,b were found to be inactive at a concentration of 100 microM, while the FUdR conjugates 5a,b exhibited IC50 values within a range of 0.30-0.40 microM. Stability studies revealed that > 99% of the phosphoramidates remained intact after incubation for > 2 days in 20% calf or 20% human serum. Intracellular thymidylate synthase (TS) inhibition studies revealed that treatment of L1210 and CCRF-CEM cells with 5a or 5b resulted in significant inhibition of TS in intact and permeabilized cells, while treatment of L929 TK- cells with these compounds did not result in inhibition of TS activity in intact cells. However, permeabilization of L929 TK- cells enhanced the activity of 5a,b toward intracellular TS by 900- and 1500-fold, respectively. In addition, incubation of cell-free extracts of CEM cells with radiolabeled 5b resulted in the rapid production of FUdR 5'-monophosphate and a lag in the generation of FUdR. Consequently, it is proposed that the metabolism of the phosphoramidate diesters of FUdR in proliferating tissue proceeds through two separate enzymatic steps involving P-N bond cleavage by an unknown phosphoramidase followed by P-O bond cleavage by phosphatases such as 5'-nucleotidase.
T W Abraham; T I Kalman; E J McIntee; C R Wagner
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  39     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1996 Nov 
Date Detail:
Created Date:  1996-12-26     Completed Date:  1996-12-26     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  4569-75     Citation Subset:  IM    
Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55455, USA.
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MeSH Terms
Cell Division / drug effects
Cell Line
Cytarabine / chemistry*
Floxuridine / chemistry*
Magnetic Resonance Spectroscopy
Organophosphorus Compounds / chemical synthesis*,  chemistry,  pharmacology
Phosphoric Monoester Hydrolases / metabolism*
Thymidylate Synthase / antagonists & inhibitors
Tumor Cells, Cultured
Grant Support
Reg. No./Substance:
0/Organophosphorus Compounds; 147-94-4/Cytarabine; 50-91-9/Floxuridine; EC Synthase; EC 3.1.3.-/Phosphoric Monoester Hydrolases

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