Chemistry and antitumor evaluation of selected classical 2,4-diaminoquinazoline analogs of folic acid

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Abstract
A series of six 2,4-diaminoquinazoline analogs [5,8-dideazaaminopterin (2a) 5,8-dideazamethopterin (2b), 10-formyl-5,8-dideazaaminopterin (2c), 5,8-dideazaisoaminopterin (3a), 5,8-dideazaisomethopterin (3b) and 10-formyl-5,8-dideazaisoaminopterin] of folic acid which bear close structural resemblance to methotrexate, 1a, were synthesized by unequivocal routes. Three of these were not described previously, while complete structural characterization of the remaining compounds is presented for the first time. Each of the compounds was a potent inhibitor of dihydrofolate reductase (DHFR) from rat liver or L1210 leukemia cells having I50 [median inhibitory concentration] values in a range similar to that of 1a. A wide divergence in inhibitory activity toward the growth of human gastrointestinal adenocarcinoma or L1210 leukemia cells in vitro was observed. Compounds having a normal folate configuration at positions 9 and 10 were more inhibitory than their isomeric reversed-bridge counterparts. The N-formyl modifications were the least active of the compounds studied. Unsubstituted or N-methyl modifications competed effectively with tritiated 1a for uptake into L1210 leukemia cells, while N-formyl modifications did not. Against an L1210 cell line resistant to 1a virtue of altered transport and overproduction of DHFR, partial but not complete cross-resistance was observed for certain analogs. Of the 3 compounds [2b, 3b and 3c] selected for in vivo evaluation against L1210 leukemia in mice, two had a similar level of antitumor activity to that of 1a. The compound 5,8-dideazamethopterin, was slightly more active than 1a but at substantially reduced dose levels.

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