ara-Cytidine acylates. Use of drug design predictors in structure-activity relationship correlation

Abstract

This manuscript if one of a series of investigations into modifying the pharmacologic properties of the antitumor, antiviral, and immunosuppressive nucleoside ara-cytidine (cytarabine, Cytosar). The present paper summarizes our studies on depot ester derivatives of the nucleoside. We are able to predict with reasonable accuracy the biological activity as measured by increased life span in the L1210 leukemic mouse from a combination of two predictor variables: (1) the solubility of the ester in water and (2) its rate of hydrolysis by the mixed esterase system of animal plasma. We have tried unsuccessfully to correlate enzymatic hydrolysis rates with an alkaline hydrolysis model. Calculated Hansch partition (p) values had a correlation of r equal to 0.86 with water solubility. These p values had no additional predictive value. Based on our results, two esters were selected for clinical trial in cancer and rheumatoid arthritis.