Nucleoside conjugates. 6. Synthesis and comparison of antitumor activity of 1-β-D-arabinofuranosylcytosine conjugates of corticosteroids and selected lipophilic alcohols

Article abstract of DOI:10.1021/jm00380a004

Five new P¹-(steroid-21-yl)-P²-(1-β-D-arabinofuranosylcytosin-5'-yl)pyrophosphat es (ara-CDP-steroids), five 1-β-D-arabinofuranosylcytosine 5'-O-(alkyl)phosphates (ara-CMP-alkyl esters), and two P¹-(alkyl)-P²-(1-β-D-arabinofuranosylcytosin-5'-yl)pyrophosphate (ara-CDP-alkyl esters) have been prepared and evaluated against L1210 lymphoid leukemia in culture and in mice (C₃D₂F₁/J). These include ara-CDP-11-deoxycorticosterone, ara-CDP-cortisone, ara-CDP-corticosterone, ara-CDP-cortexolone, and ara-CDP-prednisone, ara-CMP hexadecyl ester, ara-CMP 1-cyclohexylmethyl ester, ara-CMP 1-adamantylmethyl ester, ara-CMP 2-(1-adamanthyl)ethyl ester, ara-CMP 2-chloroethyl ester, ara-CDP hexadecyl ester, and ara-CDP 1-cyclohexylmethyl ester. The in vitro antitumor results indicated that ara-CDP-steroids were as active as the previously reported ara-CMP-steroids and that ara-CMP and ara-CDP-alkyl esters were less growth inhibiting than ara-CDP-steroids and ara-C. However, the in vivo antitumor results indicated that ara-CDP-steroids were generally less effective than the previous monophosphate derivatives. Among them ara-CDP-corticosterone and the known ara-CDP-cortisol showed greater efficacy than ara-C with ILS value of 152% and 209%, respectively, at the optimal dose of 40 and 80 (mg/kg)/day for 9 days, while that of ara-C was 138% at the optimum dose of 9.2 (mg/kg)/day. Generally, ara-CMP alkyl esters, given ip to the L1210 leukemic mice, were found to be toxic and ineffective. However, ara-CDP hexadecyl ester showed marginal activity (ILS, 38%). These preliminary results support the thesis that the ara-C conjugates of this type may require a lipophilic and naturally occurring moiety for improved efficacy.