Methotrexate esters

Li Y, Kwon GS. Methotrexate esters of poly(ethylene oxide)-block-poly(2-hydroxyethyl-L-aspartamide). Part 1 Effects of the level of methotrexate conjugation on the stability of micelles and on drug release. Pharm Res 2000 17 607-611. 

PAMAM G5 Acetyl and folate Methotrexate Ester Cancer No Yes Yes 306, 311... 

Nixon JS (1997) The biology of protein kinase C inhibitors. In Molecular Biology Intelligence Unit Protein Kinase C, PJ Parker and LV Dekker (eds.), R.G. Landes Company, Austin, TX, Springer-Verlag, Heidelberg, 205-236 Noe V, Ciudad CJ (1995) Protein kinase C inhibitors reduce phorbol ester-induced resistance to methotrexate in Chines hamster ovary cells. Biochem Pharmacol 50 337-346... 

Fig. 7. Synthesis of selectively protected methotrexate (MTX) derivative. The synthesis of ten-butyl ester of the ot-carboxyl group of the glutamic acid moiety in MTX from APA (4-amino-4-deoxy-N10-methylpteroic acid), an MTX precursor (according to [148])...

Piper, J.R. et al. (1982) Syntheses of alpha- and gamma-substituted amides, peptides, and esters of methotrexate and their evaluation as inhibitors of folate metabolism, J. Med. Chem. 25, 182-187. Wright, J.E. et al. (1993) Methotrexate and gamma-tert-butyl methotrexate transport in CEM and CEM/MTX human leukemic lymphoblasts, Biochem. Pharmacol. 46, 871-6. 

These examples are unusual in that vaiacyciovir is an amino acid ester of a nucleoside that does not closely resemble the normal dipeptide substrates of the PEPT-1 transporter. A number of other drugs (such as methotrexate) are probably transported by proteins that normally transport the metabolites that they resemble and antagonize (e.g., folates). However, these cases represent fortuitous examples of drug transportability Tiatural selection" during the drug discovery and development process. With increased understanding of the specificity determinants of... 

Similarly facilitating lipophilizing ester moieties are introduced into highly water-soluble cytostatic antimetabolites, such as methotrexate and derivatives, and into cytarabine in order to enhance penetration of the blood-brain barrier and thus to reach malignant tissue located in the CNS, which is normally out of reach for cytostatics162,163. ... 

Johns, D. G., Farquhar, D., Chabner, B. A., Wolpert, M. K., Adamson, R. H. Anti-neoplastic activity of lipid-soluble dialkyl esters of methotrexate. Experientia 29, 1104(1973). 

Beardsley, G. R, Rosowsky, A. Effect of methotrexate i-monohexa-decyl ester ("i-MHxMTX) on nucleoside uptake by human leukemic cells.ln Proc. Am. Assoc. Cancer Res. 21, 71 Meeting, 1980, p. 264. 

Soft Dihydrofolate Reductase (DHFR) Inhibitors. A series of esters was synthesized recently as possible dihydrofolate reductase (DHFR)inhibitors that are susceptible toward hydrolytic degradation (148,206-208). DHFR is involved in the reduction of dihydrofolate into tetrahydrofolate, and reduced folates are important cofactors in the biosynthesis of nucleic acids and amino acids. Hence, DHFR inhibitors can limit cellular growth. Consequently, classical DHFR inhibitors such as methotrexate (99) (Fig. 15.24) or nonclassical DHFR inhibitors such as trimetrexate (100) have shown antineoplastic or antiprotozoal... 

The methotrexate (MTX) analog (145) is prepared by condensing pyridopyrimidone carboxylic acid (143) with glutamic acid dimethyl ester (144). Testing of amide 145 in vitro against CCRF-CEM leukemia cells revealed that it is... 

Lipophilic prodrugs can also be derived from a carboxylic function, the most commonly used derivatives being carboxylic esters. Simple esters of aliphatic alcohols are attractive as they are cheap to prepare, chemically stable, and yield harmless hydrolysis products." Typical representatives of such prodrugs are tyrosine methyl ester," levodopa ethyl ester," nipecotic acid ethyl ester," enala-prilat ethyl ester," " " trandolapril," y-aminobutyric acid cetyl ester" " and methotrexate cetyl ester." ... 

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