Molecular Pharmacology, Vol 8, 740-750, Copyright © 1972 by the American Society for Pharmacology and Experimental Therapeutics

Isohomoaminopterin and Isohomofolic Acid

Synthesis and Basic Biochemical and Biological Properties

K. SLAVÍK ¹, R. CIHA ¹, J. SOUEK ¹, E. HERMANOVÁ ¹, K. PISTOUPILOVÁ ¹, and V. SLAVÍKOVÁ ¹

¹ Laboratory of Protein Metabolism and Institute of Hematology and Blood Transfusion, Prague, Czechoslovakia

Two new analogues of folic acid, isohomofolic acid and isohomoaminopterin, have been synthesized. Both compounds were prepared by reductive condensation of corresponding pteridine-6-carboxaldehydes with p-aminomethylbenzoylglutamic acid diethyl ester. Both compounds proved to be inhibitors of both HeLa and Sarcoma 180 cells in tissue culture, and also inhibited the growth of Lactobacillus casei and Streptococcus faecium. Isohomoaminopterin penetrated into Sarcoma 180 cells, whereas uptake of isohomofolic acid was not observed. The effects of both compounds on formiminotransferase, tetrahydrofolate formylase, dihydrofolate reductase, thymidylate synthetase, and the biosynthesis of inosinic acid were tested. Of all these enzymes only dihydrofolate reductase was inhibited; the inhibition was competitive with respect to folate and dihydrofolate. The inhibition by isohomoaminopterin (K_i = 12 nM with folate at pH 5.5) was two orders of magnitude greater than that by isohomofolate.