Abstract
Three groups of quinazoline analogues of folic acid were studied as inhibitors of thymidylate synthetase (TMP synthetase) from L. casei and the mouse leukemia cell line, L1210. Several of these compounds were also tested as inhibitors of cell growth using selected mammalian tumor lines. The three groups of compounds studied were classical 2-amino-4-hydroxyquinazolines, classical 2,4-diaminoquinazolines, and 5,8-dideazapteroic acid derivatives. Of the 2-amino-4-hydroxyquinazolines, N10-methyl-5,8-dideazafolic acid (compound 4) was found to be the most potent inhibitor, in terms of ID50 values for both mammalian and bacterial TMP synthetase. In general, both the 2-amino-4-hydroxyquinazolines and the 2,4-diaminoquinazolines had lower ID50 values for the mammalian TMP synthetase than for the bacterial enzyme. The 2,4-diaminoquinazoline derivatives were better inhibitors of cell growth than the 4-hydroxy-counterparts. This effect presumably relates to the fact that they are potent inhibitors of dihydrofolate reductase. Inhibition of TMP synthetase by 4 and 5 (N10-formyl-5,8-dideazafolic acid) was competitive with respect to 5,l0-CH2-H4PteGlu, the substrate; methotrexate and the compound 21, (5,8-deazaisoaminopterin) were non-competitive inhibitors with respect to 5,l0-CH2-H4PteGlu.
ACKNOWLEDGMENTS We wish to acknowledge with gratitude the assistance of Ms. Cy Webb and the helpful suggestions of Drs. C. Lindquist and B. Dolnick.
- Copyright © 1979 by Academic Press, Inc.
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