| Synthesis and biological evaluation of DL-4,4-difluoroglutamic acid and DL-gamma,gamma-difluoromethotrexate. | |
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MedLine Citation:
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PMID: 8568828 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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DL-4,4-Difluoroglutamic acid (DL-4,4-F2Glu) and its methotrexate analogue, DL-gamma,gamma-difluoromethotrexate (DL-gamma,gamma-F2MTX), were synthesized and evaluated as alternate substrates or inhibitors of folate-dependent enzymes. Synthesis of DL-4,4-F2Glu involved the nitroaldol reaction of ethyl nitroacetate with a difluorinated aldehyde ethyl hemiacetal as a key step. Attempted ligation of DL-4,4-F2Glu to methotrexate (MTX), catalyzed by human folylpoly-gamma-glutamate synthetase (FPGS), revealed that DL-4,4-F2Glu is a poor alternate substrate. DL-gamma,gamma-F2MTX was synthesized by a route proceeding through N-[4-(methylamino)benzoyl]-4,4-difluoroglutamic acid di-tert-butyl ester followed by alkylation with 6-(bromomethyl)-2,4-pteridinediamine hydrobromide. DL-gamma,gamma-F2MTX was found to be neither a substrate nor an inhibitor of human FPGS. The fluorinated analogue of MTX, however, inhibits DHFR and cell growth with the same potency as MTX. |
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Authors:
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T Tsukamoto; T Kitazume; J J McGuire; J K Coward |
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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 Jan |
Date Detail:
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Created Date: 1996-03-01 Completed Date: 1996-03-01 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: 66-72 Citation Subset: IM |
Affiliation:
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Department of Medicinal Chemistry, University of Michigan, Ann Arbor 48109, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aminopterin
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metabolism Cell Division / drug effects Cell Line Chromatography, High Pressure Liquid Folic Acid Antagonists / chemical synthesis*, metabolism, pharmacology Glutamates / chemical synthesis*, pharmacology* Glutamic Acid / metabolism Humans Kinetics Magnetic Resonance Spectroscopy Methotrexate / analogs & derivatives*, chemical synthesis, metabolism, pharmacology Molecular Structure Peptide Synthases / antagonists & inhibitors, metabolism Tetrahydrofolate Dehydrogenase / metabolism Tumor Cells, Cultured |
| Grant Support | |
ID/Acronym/Agency:
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CA13038/CA/NCI NIH HHS; CA16056/CA/NCI NIH HHS; CA28097/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Folic Acid Antagonists; 0/Glutamates; 0/gamma,gamma-difluoromethotrexate; 130835-20-0/4,4-difluoroglutamic acid; 54-62-6/Aminopterin; 56-86-0/Glutamic Acid; 59-05-2/Methotrexate; EC 1.5.1.3/Tetrahydrofolate Dehydrogenase; EC 6.3.2.-/Peptide Synthases; EC 6.3.2.17/folylpolyglutamate synthetase |
| Comments/Corrections | |
Erratum In:
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J Med Chem 1996 Sep 27;39(20):4134 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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