Irreversible Enzyme Inhibitors LXXXVI Hydrophobic Bonding to Dihydrofolic Reductase VIII. Substituted-l-aryl-4,6-diamino-1,2-dihydro-~,~-dimethyl-~-triazines By B. R. BAKER, BENG-THONG HO, a n d GERHARDUS J. LOURENS A series of l-phenyl-4,6-diamino-1,2-dihydro-2,2-dimethyl-s-triazines (IV) bearing a phenylalkyl group on the m-orp-position of the 1-phenyl moiety was synthesized for enzymic evaluation with dihydrofolic reductase. The largest increment in binding was observed with a m-phenylbutyl group (XIV) which gave a fortyfold increment in binding; activity was not increased by substitution of one or two chlorines on the terminal phenyl group. The most active compound (XIV) was complexed one-third as well as the potent aminopterin, that is, XIV had 95 per cent of the free energy of binding shown by aminopterin. The potential use of XIV and related compounds for treatment of tumors with an impaired active-transport system for folk acid and aminopterin is discussed.
METHOPTERIN (I) has been useful for the
A treatment of leukemia in children for a number of years (1); unfortunately, only about 20% of the cases respond, and then only a temporary remission occurs. Amethopterin (I) and aminopterin ( ) pass through a cell wall by active-transport (2-8), presumably by the same active-transport system used by a cell for folic acid. By use of tritiated amethopterin, Bertino (9) has been able to correlate the 20% of patients responding to amethopterin with ability of the patients' leukemic cells to take up the drug; the 70% showing no response to amethopterin had virtually no uptake of amethopterin in their leukemic cells. NH2 N&67 C H 2 1 & ) CONH CH I COOH NH& (CH2)zCOOH I,R=CHs I I , R = H I11 Citrovorum factor (5-formyl-tetrahydrofolic acid, CF) is used as an antidote for amethopterin toxicity, since C F can be utilized by a cell in place of tetrahydrofolic acid-the product of the reaction catalyzed by folic reductase which is