title: Synthesis and antifolate properties of 10-alkyl-8,10-dideazaminopterins.
abstract: The synthesis of 10-alkyl analogues of the potent antitumor agent 8,10-dideazaminopterin is described. Alkylation of appropriate alpha-alkyl homoterephthalate esters with 2,4-diamino-6-(bromomethyl)-8-deazapteridine afforded 10-alkyl-10-carboxy-4-amino-4-deoxy-8,10-dideazapteroic acid diesters. Ester cleavage and decarboxylation at C-10 were accomplished by heating with sodium cyanide in Me2SO at 170-180 degrees C to afford the 2,4-diamino-10-alkyl-8,10-dideazapteroic acids. The acids were coupled with diethyl glutamate, followed by saponification, to give the 10-alkyl-8,10-dideazaminopterins. The compounds were potent inhibitors of growth in folate-dependent bacteria, Streptococcus faecium and Lactobacillus casei. The 10-methyl and 10-ethyl analogues gave the highest percent increases in life span for mice infected with L1210 leukemia with ILS values of +203 and +235%, respectively.
mesh_terms: D000630:Aminopterin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis; D005493:Folic Acid Antagonists / Q000138:chemical synthesis*; D007939:Leukemia L1210 / Q000188:drug therapy; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D013940:Thymidylate Synthase; D000630:Aminopterin; D008727:Methotrexate