- Lysine and Ornithine Analogues of Methotrexate as Inhibitors of Dihydrofolate Reductase
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The ornithine (6a) and lysine (6b) analogues of methotrexate (1) have been synthesized via condensation of 4-amino-4-deoxy-N10-methylpteroic acid (2) with Nδ-carbobenzoxy-L-ornithine tert-butyl ester (3a) and Nε-carbobenzo
- Kempton, Robert J.,Black, Angelique M.,Anstead, Gregory M.,Kumar, A. Ashok,Blankenship, Dale T.,Freisheim, James H.
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p. 475 - 477
(2007/10/02)
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- Methotrexate analogues. 15. A methotrexate analogue designed for active-site-directed irreversible inactivation of dihydrofolate reductase
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N(a)-(4-Amino-4-deoxy-N10-methylpteroyl)-N4-(iodoacetyl)-L-lysine (1) was synthesized as a potential active-site-directed irreversible inhibitor or dihydrofolate reductase (DHFR). In an ultraviolet spectrophotometric assay of dihydrofolate reduction by Lactobacillus casei DHFR, 1 and methotrexate (MTX, 4-amino-4-deoxy-N10-methylpteroyl-L-glutamic acid) had ID50 values of 4.5 and 6.2 nM. The corresponding ID50 values in a competitive radioligand binding assay against [3H]MTX were 31 and 16 nM. Thus, as reversible inhibitors of this enzyme over a short exposure time, 1 and MTX had comparable activity. On the other hand, when L. casei DHFR was incubated for up to 6 h with 0.1 or 1.0 μM 1, a progressive decrease in the ability of [3H]MTX to subsequently displace the drug was observed. When MTX itself was used at the same concentrations, the extent of displacement of [3H]MTX did not decrease with time. These results were consistent with rapid reversible binding of 1 to the enzyme, followed more slowly by covalent bond formation near the active site. The pH profile for this effect followed a curve with a sigmoidal shape. The apparent inflection point near pH 7.2 was consistent with alkylation of a histidine residue.
- Rosowsky,Wright,Ginty,Uren
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p. 960 - 964
(2007/10/02)
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- Folic acid antagonists. Methotrexate analogs containing spurious amino acids. Dichlorohomofolic acid
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The synthesis and some biological testing results are reported for dichlorohomofolic acid (2a) and 3 methotrexate (MTX) analogs in which the L glutamic acid moiety was replaced by D glutamic acid, glutaric acid, and L lysine to give 4b, 4c, and 4d, respec
- Lee,Martinez,Goodman
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p. 326 - 330
(2007/10/06)
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