| Abstract: |
Synthesis of the 10-methyl and 10-ethyl analogues of 5,10-dideazatetrahydrofolic acid (DDTHF), a potent inhibitor of glycinamide ribotide (GAR) formyltransferase, is reported. Key intermediates in the process were 10-methyland 10-ethyl-4-amino-4-deoxy-5,10-dideazapteroic acid. Condensation of the piperidine enamines of branched 4-(p-carbomethoxyphenyl)butyraldehydes with (acetoxymethylene)malononitrile afforded l,l-dicyano-4-piperidi-nobutadiene 5a,b. Subsequent reaction with alcoholic ammonium hydroxide yielded the appropriately substituted 2-amino-3-cyanopyridines 6a,b. Ring closure with guanidine gave 10-methyl- and 10-ethyl-4-amino-4-deoxy-5,10-dideazapteroic acids (7a,b). Coupling with diethyl glutamate followed by ester hydrolysis afforded 10-alkyl-5,10-dideazaminopterin analogues 9a,b. Hydrolysis of the 4-amino group of 7a,b yielded the 10-alkylpteroic acids, which were coupled with diethyl glutamate, hydrogenated over PtO2, and saponified to afford 10-alkyl-5,10-dideaza-tetrahydrofolic acids 13a,b. Aminopterin analogues 9a,b were effective inhibitors of DHFR derived from L1210, but were less potent than methotrexate for inhibition of growth of L1210 in culture. The 10-ethyl (13b) analogue of 5,10-DDTHF was about twice as potent an inhibitor of L1210 cell growth as 5,10-DDTHF, but was only 1/7 as potent for inhibition of GAR formyltransferase. 10-Methyl analogue 13a was similar in potency to 5,10-DDTHF. All of the compounds showed moderately improved transport into L1210 cells relative to methotrexate. © 1990, American Chemical Society. All rights reserved. |
| Keywords: |
unclassified drug; nonhuman; methotrexate; mass spectrometry; animal; mice; cell division; antimetabolites, antineoplastic; drug screening; tumor cells, cultured; drug synthesis; drug uptake; dihydrofolate reductase; folic acid antagonists; nuclear magnetic resonance; methotrexate derivative; acyltransferases; tetrahydrofolates; leukemia l1210; priority journal; article; ultraviolet spectrophotometry; support, u.s. gov't, p.h.s.; leukemia l 1210; phosphoribosylglycinamide formyltransferase; 5,6,7,8 tetrahydro 10 methyl 5,10 dideazafolic acid; tetrahydrofolic acid derivative
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