NUCLEOSIDE CONJUGATES AS POTENTIAL ANTI-TUMOR AGENTS .2. SYNTHESIS AND BIOLOGICAL-ACTIVITY OF "1-(BETA-D-ARABINOFURANOSYL)CYTOSINE CONJUGATES OF PREDNISOLONE AND PREDNISONE

Two of the new anticancer drugs recently synthesized in our laboratory from conjugation of ara-C2 and several corticosteroids linked through a phosphodiester bond include prednisolone-(I) and prednisone-p-ara-C (II). They were demonstrated to be enzymatically hydrolyzed to the corresponding steroid and ara-CMP and the latter was further shown to be hydrolyzed to ara-C by phosphodiesterase I, snake venom, 5-nucleotidase, and acid phosphatase. However, the conjugates were shown to be resistant to hydrolysis by alkaline phosphatase. The activity of conjugates I and II against L1210 lymphoid leukemia in female mice (C3D2F1/J) was significantly greater than that of ara-C alone or in combination with the steroid. In fact, when the optimum dosage of 75 (μmol/kg)/day X 5 was used, the administration of ara-C alone was followed by an increased life span (ILS) of 45%. This result is similar to that previously reported.3 With the same equimolar doses of mixtures of ara-C and either prednisolone or prednisone, the ILS values were 40 and 44%, respectively. However, when the conjugates were used, the ILS values were 89 and 100%, respectively. These findings seem promising and have provided the bases for continued study of these new compounds. © 1979, American Chemical Society. All rights reserved.