title: Sulfamide antifolates inhibiting thymidylate synthase: synthesis, enzyme inhibition and cytotoxicity.
abstract: Synthesis and biological evaluation are described of seven new analogues (3-9) of two potent thymidylate synthase inhibitors, 10-propargyl-5,8-dideazafolate (1) and its 2-methyl-2-deamino congener ICI 198583 (2). While the new compunds 3 and 4 were analogues of 1 and 2, respectively, containing a p-aminobenzenesulfonyl residue in place of the p-aminobenzoic acid residue, the remaining 5 new compounds were analogues of 4 with the L-glutamic acid residue replaced by glycine (5), L-valine (6), L-alanine (7), L-phenylglycine (8) or L-norvaline (9). The new analogues were tested as inhibitors of thymidylate synthases isolated from tumour (Ehrlich carcinoma), parasite (Hymenolepis diminuta) and normal tissue (regenerating rat liver) and found to be weaker inhibitors than the parent 10-propargyl-5,8-dideazafolic acid. Selected new analogues, tested as inhibitors of growth of mouse leukemia L 5178Y cells, were less potent than the parent 10-propargyl-5,8-dideazafolic acid. Substitution of the glutamyl residue in compound 4 with L-norvaline (9) resulted in only a 5-fold stronger thymidylate synthase inhibitor, but a 40-fold weaker cell growth inhibitor.
mesh_terms: D000818:Animals; D002286:Carcinoma, Ehrlich Tumor / Q000201:enzymology / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D013449:Sulfonamides; D013940:Thymidylate Synthase