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Synthesis and characterization of polymeric derivatives of the folic acid antagonist, Methotrexate, N-[4-(N-methyl-2,4-diamino-6-pteridinylmethylamino)benzoyl] glutamic acid (1a), a widely used antitumor agent, are described. Derivatives of poly(L-lysine), poly(iminoethylene), poly(vinyl alcohol), and carboxymethylcellulose with various contents (3–15 mole-%) of substituted repeating units were prepared by polymer-analogous amidation and transesterification of the dimethyl ester of 1a and with N-[2-(N-methylmorpholinio)ethyl]carbodiimide p-toluenesulfonate as coupling reagent. By nucleophilic addition reactions of the pteridinyl amino groups under mild conditions, 1a was bound without cross-linking to divinyl ether-maleic anhydride (DIVEMA) copolymers of various molecular weights. This copolymer appeared to be of particular interest as carrier because of its established antitumor and immune-stimulating activity.—With the exception of the poly(vinyl alcohol) derivative, all polymers containing the 1a residue are water soluble at the physiological pH range. Besides the dimethyl ester of 1a used as convenient starting material for polymer-analogous reactions, further dialkyl esters of 1a were synthesized as low molecular weight model compounds for the study of the pharmacodynamic properties of polymers, substituted with 1a. The polymeric derivatives of 1a were purified by membrane filtration, solvent extraction, and reprecipitation; the polymers and the dialkylesters 1b–d were characterized by thin-layer chromatography, IR, NMR, UV and mass spectra, and elemental analysis. Preliminary results of the pharmacological studies with the DIVEMA derivatives of 1a are also reported.