| Synthesis and biological evaluation of poly-gamma-glutamyl metabolites of 10-deazaaminopterin and 10-ethyl-10-deazaaminopterin. | |
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MedLine Citation:
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PMID: 2447278 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The chemical synthesis of a series of poly-gamma-glutamyl metabolites of the experimental anticancer drugs 10-deazaaminopterin (10-DAAM) and 10-ethyl-10-deazaaminopterin (10-EDAAM) has been carried out by the solid-phase procedure. The synthetic products were identical with the poly-gamma-glutamyl metabolites of radiolabeled 10-DAAM and 10-EDAAM produced by normal mouse tissues with regard to elution volume from [(diethylamino)ethyl]cellulose columns and susceptibility to hydrolysis by human plasma folylpolyglutamate hydrolase. Poly-gamma-glutamyl metabolites with a glutamate chain length of up to four glutamate residues were detected in the tissues. The antifolate activity was evaluated with methotrexate (MTX) sensitive and MTX-resistant strains of Lactobacillus casei and Streptococcus faecium. In general, inhibitory potency decreases with increasing Glu chain length. However there are two exceptions. Addition of one Glu residue to 10-DAAM enhances its potency for MTX-resistant L. casei and addition of one Glu residue to 10-EDAAM enhances its potency for the MTX-sensitive L. casei. As shown earlier for MTX polyglutamates, polyglutamylation greatly enhances the inhibitory potency of 10-DAAM and 10-EDAAM for L. casei thymidylate synthase. MTX polyglutamates are 15-30 times more inhibitory than the corresponding 10-DAAM derivatives and 30-60 times more inhibitory than the corresponding 10-EDAAM derivatives. Polyglutamylation of 10-DAAM had little influence on its ability to inhibit L. casei dihydrofolate reductase; however, with 10-EDAAM, addition of one or two Glu residues enhanced its inhibitory potency 2.3-fold. |
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Authors:
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M G Nair; N T Nanavati; P Kumar; Y Gaumont; R L Kisliuk |
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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: 31 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1988 Jan |
Date Detail:
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Created Date: 1988-02-17 Completed Date: 1988-02-17 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: 181-5 Citation Subset: IM |
Affiliation:
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Department of Biochemistry, University of South Alabama, Mobile 36688. |
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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analogs & derivatives*,
pharmacology Animals Anti-Bacterial Agents / chemical synthesis* Female Folic Acid Antagonists / pharmacology* Humans Lactobacillus casei / drug effects Methotrexate / pharmacology Mice Mice, Inbred Strains Microbial Sensitivity Tests Peptides / chemical synthesis* Polyglutamic Acid / analogs & derivatives, chemical synthesis*, pharmacology Streptococcus / drug effects Structure-Activity Relationship Substrate Specificity gamma-Glutamyl Hydrolase / blood |
| Grant Support | |
ID/Acronym/Agency:
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CA 10914/CA/NCI NIH HHS; CA 27101/CA/NCI NIH HHS; CA 32687/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-Bacterial Agents; 0/Folic Acid Antagonists; 0/Peptides; 25513-46-6/Polyglutamic Acid; 52454-37-2/10-deazaaminopterin; 54-62-6/Aminopterin; 59-05-2/Methotrexate; 80576-83-6/edatrexate; EC 3.4.19.9/gamma-Glutamyl Hydrolase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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