Isolation, characterization, and properties of a labile hydrolysis product of the antitumor nucleoside, 5-azacytidine

Publisher Website
Google Scholar
Abstract
The antitumor nucleoside, 5-azacytidine (5-AC), is best administered clinically by prolonged i.v. infusion to minimize toxic effects. In opposition to this administration technique is facile drug decomposition in aqueous formulations giving products of unknown toxicity. Analysis of 24-h-old water solutions of 5-AC with high-pressure liquid chromatography (HPLC) indicated a 3-fold mixture of 5-AC, N-(formylamidino)-N''-.beta.-D-ribofuranosylurea (RGU-CHO), and 1-.beta.-D-ribofuranosyl-3-guanylurea (RGU). Preparative HPLC allowed the isolation and subsequent identification of each component in the mixture, including RGU-CHO which, was not previously available for chemical and biological study. RGU-CHO in water solution readily equilibrates to 5-AC and more slowly deformylates to give RGU irreversibly. The latter hydrolysis product exhibited no pronounced toxicity when tested in vitro or in vivo. Although RGU-CHO showed considerable antitumor activity against mouse L1210 leukemia, hydrolysis studies indicated that all observed activity could be attributed to 5-AC formed by in vivo equilibration from RGU-CHO. RGU-CHO seemed to impart to test animals a toxicity which was no greater than that anticipated from its ability to generate 5-AC.

This publication has 1 reference indexed in Scilit: