Methotrexate analogues. 12. Synthesis and biological properties of some aza homologues

Methotrexate analogues, in which an additional nitrogen atom is inserted between the phenyl ring and the carbonyl group of the side chain, were prepared by photochemical methods. The compounds were less inhibitory toward dihydrofolate reductase and thymidylate synthetase derived from Lactobacillus c...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1979-07, Vol.22 (7), p.869-874
Main Authors: Martinelli, J E, Chaykovsky, M, Kisliuk, R L, Gaumont, Y, Gittelman, M C
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - therapeutic use
Folic Acid Antagonists
Humans
In Vitro Techniques
Lactobacillus casei - drug effects
Lactobacillus casei - enzymology
Lactobacillus casei - growth & development
Leukemia L1210 - drug therapy
Leukemia, Lymphoid - drug therapy
Male
Methods
Methotrexate - analogs & derivatives
Methotrexate - chemical synthesis
Methotrexate - pharmacology
Methotrexate - therapeutic use
Mice
Thymidylate Synthase - antagonists & inhibitors
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Summary:Methotrexate analogues, in which an additional nitrogen atom is inserted between the phenyl ring and the carbonyl group of the side chain, were prepared by photochemical methods. The compounds were less inhibitory toward dihydrofolate reductase and thymidylate synthetase derived from Lactobacillus casei than was methotrexate. They were also less cytotoxic against human lymphoblastic leukemia cells (CCRF-CEM). In vivo against L-1210 leukemia in mice, the aza homologue of methotrexate showed significant antitumor activity (%ILS = 55%) compared to methotrexate (%ILS = 88%).
ISSN:0022-2623
DOI:10.1021/jm00193a022