Folate analogs altered in the C9-N10 bridge region. 18. Synthesis and antitumor evaluation of 11-oxahomoaminopterin and related compounds

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Abstract
The chemical synthesis of 11-oxahomoaminopterin (1) was carried out using procedures which were applicable to the synthesis of 11-oxahomofolic acid. Reaction of 1-bromo-4-[p-(carbomethoxy)phenoxy]-2-butanone with sodium azide gave 1-azido-4-[p-(carbomethoxy)phenoxy]-2-butanone (11). Protection of the carbonyl group of 11 as the ethylene ketal and subsequent base hydrolysis of the product gave 1-azido-4-(p-carboxyphenoxy)-2-butanone ketal (13). The glutamate conjugate 14 was prepared from 13 by the isobutyl chloroformate method and was hydrogenated to diethyl N-[(.alpha.-amino-2-oxo-4-butanoyl)-p-anisoyl]-L-glutamate ketal (15). Although 11-oxahomoaminopterin showed antifolate activity against 2 folate requiring microorganisms and inhibited Lactobacillus casei dihydrofolate reductase, it was inactive againt L-1210 leukemia in mice at a maximum dose of 48 mg/kg. Compound 1 was also tested for its ability to be transported via the methotrexate transport system using the L-1210 and Ehrlich ascites tumor cell lines and these results are compared with those of related analogs. The growth inhibitory activity of 1 in the L-1210 cells lines in culture was 15 times weaker than that of methotrexate.