102651-06-9Relevant articles and documents
Methotrexate Analogues. 28. Synthesis and Biological Evaluation of New γ-Monoamides of Aminopterin and Methotrexate
Rosowsky, Andre,Bader, Henry,Radike-Smith, Mary,Cucchi, Carol A.,Wick, Michael M.,Freisheim, James H.
, p. 1703 - 1709 (2007/10/02)
Lipophilic γ-monoamide derivatives of aminopterin (AMT) were synthesized in high overall yield from 4-amino-4-deoxyN10-formylpteroic acid and γ-N-tert-alkyl-, γ-N-aralkyl, or γ-N-arylamides of α-benzyl L-glutamate via a modification of the mixed carboxylic-carbonic anhydride coupling method.Coupling was also accomplished with p-nitrophenyl 4-amino-4-deoxy-N10-formylpteroate.Compounds obtained in this manner included the γ-tert-butylamide, γ-(1-adamantylamide), γ-benzylamide, γ-(3,4-dichlorobenzylamide), γ-(2,6-dichlorobenzylamide, γ-anilide, γ-(3,4-methylened ioxyanilide), and γ-(3,4-dihydroxanilide) derivatives of AMT.Also prepared, from 4-amino-4-deoxy-N10-methylpteroic acid via diethyl phosphorocyanidate coupling, was the γ-(3,4-methylenedioxyanilide) of MTX.The methylenedioxyanilides were cleaved smoothly dihydroxyanilides with boron tri(trifluoroacetate) in trifluoroacetic acid.All the γ-monoamides were tested as inhibitors of purified dihydrofolate reductase (DHFR) from murine L1210 leukemia cells and as inhibitors of the growth of wild-type L1210 cells and a subline (L1210/R81) with high-level resistance to MTX and AMT based mainly on a defect in drug uptake via active transport.Several compounds were also tested against human leukemic lymphoblasts (CEM cells) and a resistant subline (CEM/MTX) whose resistance is like wise based on uptake.The IC50 of the γ-monoamides against DHFR was 1.5- to 5-fold higher than that of the parent acids, but the IC50 against cultured cells varied over a much broader range, suggesting that uptake and/or metabolism rather than DHFR binding are principal determinants of in vitro growth inhibitory activity for these compounds. γ-N-Aryl and γ-N-aralkyl derivatives appeared to be more potent than γ-N-tert-alkyl derivatives.Where comparison could be made, AMT γ-monoamides were more potent than MTX γ-monoamides.Several of the γ-monoamides showed potency comparable to that of the parent acid against wild-type L1210 and CEM cells; all of them were more potent than MTX against the L1210/R81 subline; and some of the AMT γ-monoamides were also more potent than the parent acid against resistant CEM/MTX cells.As a group, however, the γ-monoamides were considerably more active against the murine cells than against the human cells, suggesting that the former may take up the amides better or may be able to metabolize them more efficiently than the parent acids.All the γ-monoamides were tested in vivo against L1210 leukemia in mice.The γ-N-tert-alkylamides were inactive, whereas significant activity (>50percent increase in survival at optimal doses) was shown by every γ-N-aralkylamide and γ-N-arylamide in the series.The γ-N-arylamides were more toxic than the γ-N-aralkylamides.The most therapeutically effective compound was AMT γ-(3,4-dichlorobenzylamide), which produced an increase in lifespan (ILS) of 110percent at 70 mg/kg per day x 9 as compared with 122percent fot AMT itself at 0.5 mg/kg per day x 9.The fact that...
