| Abstract: |
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-dideazatetra-hydropteroic 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. © 1986, American Chemical Society. All rights reserved. |
| Keywords: |
unclassified drug; nonhuman; methotrexate; mass spectrometry; animal cell; mouse; animals; mice; cell division; in vitro study; drug screening; drug synthesis; chemistry; folic acid; drug cytotoxicity; dihydrofolate reductase; thymidylate synthase; folic acid antagonists; drug sensitivity; nuclear magnetic resonance; aminopterin; drug identification; intoxication; streptococcus; leukemia l1210; enterococcus faecalis; new drug; priority journal; article; ultraviolet spectrophotometry; leukemia l 1210; lactobacillus casei; blood and hemopoietic system; drug analysis; 5,10 carbonyl 5,6,7,8 tetrahydro 8,10 dideazaaminopterin; 5,6,7,8 tetrahydro 5,10 methylene 8,10 dideazaaminopterin
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