Methotrexate analogues. 16. Importance of the side-chain amide carbonyl group as a structural determinant of biological activity.
N-[[[(2,4-Diaminopteridin-6-yl)methyl]amino]benzyl]-L-glutamic acid ("deoxoaminopterin", 1), a new aminopterin analogue containing a CH2 group in the side chain in place of the amide C = O, was synthesized by condensation of 2,4-diamino-6-(bromomethyl)pteridine with diethyl N-(p-aminobenzyl)-L-glutamate, followed by saponification with a stoichiometric amount of barium hydroxide in 50% ethanol. The apparent importance of the amide C = O group as a structural determinant of biological activity was indicated by the finding that 1 has 10- to 20-fold lower affinity for bacterial and mammalian dihydrofolate reductase than aminopterin, is not toxic to L1210 murine leukemia cells in culture at a concentration of up to 1.0 microM, and shows no antitumor effect in L1210 leukemic mice at doses as high as 240 mg/kg (q3d X 3).
D000818:Animals; D001667:Binding, Competitive; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D005493:Folic Acid Antagonists; D007780:Lacticaseibacillus casei / Q000201:enzymology; D007939:Leukemia L1210 / Q000201:enzymology; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship
D005493:Folic Acid Antagonists; D008727:Methotrexate