Synthesis and in Vitro Antifolate Activity of Rotationally Restricted Aminopterin and Methotrexate Analogues

Heretofore unknown analogues of aminopterin (AMT) and methotrexate (MTX) in which free rotation of the amide bond between the phenyl ring and amino acid side chain is prevented by a CH2 bridge were synthesized and tested for in vitro antifolate activity. The K i of the AMT analogue (9) against human...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2004-12, Vol.47 (27), p.6958-6963
Main Authors: Rosowsky, Andre, Forsch, Ronald A, Wright, Joel E
Format: Article
Language:English
Subjects:
Aminopterin - analogs & derivatives
Aminopterin - chemical synthesis
Aminopterin - pharmacology
Antineoplastic agents
Biological and medical sciences
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Folic Acid Antagonists - chemical synthesis
Folic Acid Antagonists - pharmacology
General aspects
Humans
Magnetic Resonance Spectroscopy
Medical sciences
Methotrexate - analogs & derivatives
Methotrexate - chemical synthesis
Methotrexate - pharmacology
Pharmacology. Drug treatments
Structure-Activity Relationship
Tetrahydrofolate Dehydrogenase - metabolism
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Summary:Heretofore unknown analogues of aminopterin (AMT) and methotrexate (MTX) in which free rotation of the amide bond between the phenyl ring and amino acid side chain is prevented by a CH2 bridge were synthesized and tested for in vitro antifolate activity. The K i of the AMT analogue (9) against human dihydrofolate reductase (DHFR) was 34 pM, whereas that of the MTX analogue (10) was 2100 pM. Both compounds were less potent than the parent drugs. However, although the difference between AMT and MTX was
ISSN:0022-2623
1520-4804
DOI:10.1021/jm040122s