Inhibition of a methotrexate-insensitive dihydrofolate reductase from L5178Y cells by substituted triazines and quinazolines.
Inhibition by a variety of substituted triazines and quinazolines of a methotrexate-insensitive form of dihydrofolate reductase from highly MTX-resistant L5178Y mouse leukemia cells was examined. Some of these compounds were significantly more potent than MTX (up to 100-fold). Two triazenes, terminally substituted with benzenesulfonylfluoride residues, were approximately 30-fold more potent than MTX. Quinazoline analogs of folic acid with alterations in different parts of the molecule varied in their potencies as inhibitors. Although none of the compounds tested was as potent as MTX against MTX-sensitive dihydrofolate reductases, these studies show that some types of folate antagonists have increased specificity against this MTX-insensitive dihydrofolate reductase. This finding increases the likelihood that it may be possible to produce compounds with marked specificity for the insensitive reductase. Such compounds might have utility in antifolate combinations designed to overcome methotrexate resistance.
D000818:Animals; D002478:Cells, Cultured; D005493:Folic Acid Antagonists; D007940:Leukemia L5178 / Q000201:enzymology*; D007942:Leukemia, Experimental / Q000201:enzymology*; D008727:Methotrexate / Q000494:pharmacology*; D051379:Mice; D011799:Quinazolines / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*
D005493:Folic Acid Antagonists; D011799:Quinazolines; D014227:Triazines; D008727:Methotrexate