Synthesis and antifolate properties of 5,10-methylenetetrahydro-8,10-dideazaminopterin.
The synthesis of the 5,10-methylene analogue of 5,6,7,8-tetrahydro-8,10-dideazaminopterin, a potential dual inhibitor of dihydrofolate reductase (DHFR) and thymidylate synthase (TS) enzymes, is described. The dimethyl ester of 10-carboxy-4-amino-4-deoxy-8,10-dideazapteroic acid was converted to the tetrahydro derivative by hydrogenation. Thermally induced cyclization of the 10-carbomethoxy and the 5-NH groups afforded the 5,10-carbonyl analogue. Reduction of the lactam with borane readily yielded the key 5,10-methylene-4-amino-4-deoxy-8,10-dideazatetrahydropteroic acid methyl ester. Saponification of the benzoate ester and coupling with L-glutamate concluded the synthesis. The title compound was a modest inhibitor of growth in folate-dependent bacteria. Streptococcus faecium and Lactobacillus casei, but inhibition of DHFR or TS derived from L. casei was poor. The compound was also a weak inhibitor of DHFR derived from L1210 murine leukemia and was a weak inhibitor of L1210 growth in culture.
D000630:Aminopterin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D007780:Lacticaseibacillus casei / Q000187:drug effects / Q000254:growth & development; D007939:Leukemia L1210 / Q000201:enzymology / Q000473:pathology; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D013291:Streptococcus / Q000187:drug effects / Q000254:growth & development; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D005493:Folic Acid Antagonists; C050040:5,10-methylene-5,6,7,8-tetrahydro-8,10-dideazaminopterin; D013940:Thymidylate Synthase; D000630:Aminopterin; D008727:Methotrexate