| Synthesis and biological activity of aromatic amino acid phosphoramidates of 5-fluoro-2'-deoxyuridine and 1-beta-arabinofuranosylcytosine: evidence of phosphoramidase activity. | |
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MedLine Citation:
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PMID: 8917645 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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T W Abraham; T I Kalman; E J McIntee; C R Wagner |
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Publication Detail:
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Type: Journal Article; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 39 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1996 Nov |
Date Detail:
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Created Date: 1996-12-26 Completed Date: 1996-12-26 Revised Date: 2007-11-14 |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 4569-75 Citation Subset: IM |
Affiliation:
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Department of Medicinal Chemistry, University of Minnesota, Minneapolis 55455, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Division / drug effects Cell Line Cytarabine / chemistry* Floxuridine / chemistry* Humans Magnetic Resonance Spectroscopy Mice Organophosphorus Compounds / chemical synthesis*, chemistry, pharmacology Phosphoric Monoester Hydrolases / metabolism* Thymidylate Synthase / antagonists & inhibitors Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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AI 27251/AI/NIAID NIH HHS; CA 35212/CA/NCI NIH HHS; CA 61908/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Organophosphorus Compounds; 147-94-4/Cytarabine; 50-91-9/Floxuridine; EC 2.1.1.45/Thymidylate Synthase; EC 3.1.3.-/Phosphoric Monoester Hydrolases |
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