Methotrexate analogs. 21. Divergent influence of alkyl chain length on the dihydrofolate reductase affinity and cytotoxicity of methotrexate monoesters

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Abstract
N-Octyl, n-dodecyl, and n-hexadecyl .alpha.- and .gamma.-esters of methotrexate (MTX) were compared with the previously described .alpha.- and .gamma.-n-butyl esters and with MTX as inhibitors of dihydrofolate reductase (DHFR) and human leukemic lymphoblasts (CEM cells) in culture. The overall order of activity in both test systems was MTX > MTX .gamma.-esters > MTX .alpha.-esters. In the DHFR assay the activity of the .alpha.-esters followed the order C4 > C8 .simeq. C12 > C16, whereas for the .gamma.-esters this order was C4 .simeq. C8 > C12 > C16. The order of cytotoxic activity in culture in both series was C16 > C12 > C8 > C4. Increasing the alkyl chain length in the ester moiety therefore decreases DHFR affinity but increases cytotoxicity. The most potent member of the compound tested was the .gamma.-n-hexadecyl ester, whose IC50 against CEM cells was 0.11 .mu.M as compared with 0.025 .mu.M for MTX. In a comparison of the effect of treatment with the .gamma.-n-hexadecyl ester (10-5 M, 1 h) on DNA synthesis in CEM and CEM/MTX cells, the latter of which are 120-fold resistant to MTX by virtue of a transport defect, the ester produced only 4-fold less inhibition in the resistant line than in the parental line. These results suggest possible use of this compound or related derivatives in the treatment of MTX-resistant tumors with impaired transport.

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