86669-33-2Relevant articles and documents
N-(L-α-aminoacyl) derivatives of methotrexate
Cheung, H.T.Andrew,Boadle, Deborah K.,Tran, Trung Q.
, p. 751 - 758 (2007/10/02)
Methotrexate di-t-butyl ester 3 was coupled with N-t-butyloxycarbonyl-L-leucine by the p-nitrophenyl ester and carbodiimide methods to give the di-t-butyl esters 5a - 7a of 2-, 4-, and 2,4-di(N-t-butyloxycarbonyl-L-leucyl)methotrexate. The corresponding L-alanyl analogues 5b - 7b were also synthesised by the latter method. The positions of the acyl groups uere determined from 13C-nmr and uv data. Upon deprotection with trifluoroacetic acid, the 2-acyl products 5a and 5b yielded 2-L-leucyl- and 2-L-alanylmethotrexate 4a and 4b, but the 4-acyl analogues 6a and 6b gave decomposition products. The enzymic cleavage of the 2-(L-α-aminoacyl) pro-drug derivatives 4a and 4b by porcine microsomal leucine aminopeptidase was followed by high-pressure liquid-chromatography (HPLC).
Methotrexate Analogues. 18. Enhancement of the Antitumor Effect of Methotrexate and 3',5'-Dichloromethotrexate by the Use of Lipid-Soluble Diesters
Rosowsky, A.,Yu, C.-S.
, p. 1448 - 1452 (2007/10/02)
Lipophilic methotrexate (MTX) and 3',5'-dichloromethotrexate (DCM) diesters were prepared by HCl-catalyzed esterification or by neutral esterification using cesium carbonate and an alkyl or aralkyl halide in Me2SO.The products were tested for in vivo antitumor activity against L1210 leukemia in mice to test whether all MTX and DCM diesters are therapeutically equivalent in this species.Contrary to what has been found with simple primary dialkyl esters, ortho-substituted dibenzyl esters of MTX produce longer survival on a q3d*3 schedule than does MTX itself and show a dose-sparing effect comparable to that of MTX at shorter treatment intervals.Thus, MTX bis(6-chloropiperonyl) ester at an MTX-equivalent dose of 5.5 mg/kg gave a +88percent increase in median life span (ILS), whereas for MTX a +88percent ILS required 30 mg/kg.When the MTX-equivalent dose of MTX bis(6-chloropiperonyl) ester was increased to 40 mg/kg, a +167percent ILS was observed, as compared with a +100percent ILS with 60 mg/kg of the parent drug.High activity (>100percent ILS) was likewise shown by the bis(2,5-dimethylbenzyl), bis(2,6-dichlorobenzyl), and di-3-picolyl esters of MTX and by the bis(1-methylbutyl) ester of DCM.The results of this study indicate that MTX and DCM esters are not therapeutically equivalent in mice, despite the high serum esterase activity in this species, and that an up to 10-fold reduction in total administered dose on the q3d*3 schedule is feasible by this approach.
