| Methotrexate analogues. 13. Chemical and pharmacological studies on amide, hydrazide, and hydroxamic acid derivatives of the glutamate side chain. | |
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MedLine Citation:
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PMID: 6787199 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Carbodiimide-mediated condensation of 4-amino-4-deoxy-N10-methylpteroic acid (APA) with several alkyl, aralkyl, and aryl amines, in the presence or absence of N-hydroxysuccinimide, was employed in order to prepare new lipid-soluble bis(amide) derivatives of methotrexate (MTX) as potential prodrugs. MTX dianilide was likewise prepared, in comparable yield, from APA and L-glutamic acid dianilide via the mixed carboxylic--carbonic anhydride method. Dihydrazide and bis(N-methylhydrazide) derivatives of MTX were formed readily from MTX diethyl ester. However, reaction with hydroxylamine led to MTX gamma-monohydroxamic acid as the sole isolated product. The bis adduct appears to form, but is unstable during workup. The identity of the product was confirmed by independent mixed anhydride synthesis from APA and the gamma-monohydroxamate of L-glutamic acid. Treatment of MTX dimethyl ester with N,N-dimethylhydrazine unexpectedly yielded MTX gamma-monomethyl ester. MTX dianilide was active against L1210 leukemia in mice, with a +155% increase in life span at a dose of 160 mg/kg given ip in 10% Tween 80 on a q3d X 3 schedule. The bis(p-chlorobenzylamide), bis(p-methoxybenzylamide), and dihydrazide were also active against L1210 leukemia in vivo, but to a lesser extent than the dianilide. The gamma-monohydroxamic acid derivative showed activity (+111% ILS at 40 mg/kg) similar to that of MTX and was found to bind to a partially purified dihydrofolate reductase preparation from L1210 cells with an ID50 of 0.005 microM as compared to 0.007 microM for MTX. In vivo experiments in mice indicated that the pharmacokinetic properties of this compound and of MTX are similar but failed to demonstrate any advantage over MTX in terms of selective uptake into tumor (sc implanted P388 leukemia) or improved penetration of the central nervous system. The activities of the dianilide, bis(benzylamide), and dihydrazide derivatives in vivo are of interest in view of their low toxicity relative to MTX against cells in culture, which suggests that these derivatives are probably acting as prodrugs in the intact animal. |
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Authors:
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A Rosowsky; C S Yu; J Uren; H Lazarus; M Wick |
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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: 24 ISSN: 0022-2623 ISO Abbreviation: J. Med. Chem. Publication Date: 1981 May |
Date Detail:
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Created Date: 1981-08-10 Completed Date: 1981-08-10 Revised Date: 2011-12-06 |
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: 559-67 Citation Subset: IM |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amides
/
chemical synthesis,
pharmacology Animals Chemical Phenomena Chemistry Glutamates Hydrazines / chemical synthesis, pharmacology Hydroxamic Acids / chemical synthesis, pharmacology Male Methotrexate / analogs & derivatives*, chemical synthesis, pharmacology Mice |
| Grant Support | |
ID/Acronym/Agency:
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CA 06516/CA/NCI NIH HHS; CA 25394/CA/NCI NIH HHS; CH-23/CH/OID CDC HHS |
| Chemical | |
Reg. No./Substance:
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0/Amides; 0/Glutamates; 0/Hydrazines; 0/Hydroxamic Acids; 59-05-2/Methotrexate |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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