NUCLEOSIDE CONJUGATES .11. SYNTHESIS AND ANTITUMOR-ACTIVITY OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE AND CYTIDINE CONJUGATES OF THIOETHER LIPIDS

Five 1-β-D-arabinofuranosylcytosine conjugates and two cytidine conjugates of thioether lipids (1-S-alkylthioglycerols) linked by a pyrophosphate diester bond have been prepared and their antitumor activity against an ara-C2sensitive (L1210/0) and two ara-C resistant L1210 lymphoid leukemia sublines in mice were evaluated. These prodrugs of ara-C include ara-CDP-rac-l-S-hexadecyl-2-O-palmitoyl-l-thioglycerol (8a), ara-CDP-rac-l-S-octadecyl-2-O-palmitoylthioglycerol (8b), and ara-CDP-rac-l-S-octadecyl-2-O-methyl(or -ethyl, -hexadecyl)thioglycerols (8c-e). The cytidine conjugates include CDP-rac-l-S-octadecyl-2-O-palmitoyl(or -methyl)-1-thioglycerols (9a and 9b). Sonicated solutions of the conjugates existed in the form of micellar disks (size 0.01-0.04 µm). Single doses (200-400 mg/kg) of 8a and 8b produced significant increase in life span (257-371%) in mice bearing ip implanted L1210/0 leukemia. In contrast, conjugates 8c-e were less effective (ILS 19-75%) and cytidine conjugates (9a and 9b) were ineffective. Even though 8a and 8b were found to be curative in a high percentage of mice bearing ip implanted partially ara-C resistant L1210 subline [L1210/ara-C(I)], they were completely ineffective against deoxycytidine kinase deficient ara-C resistant L1210 subline [L1210/ara-C(II)]. However, the present results, together with the previous, demonstrate that 8a and 8b are promising new prodrugs of ara-C with improved efficacy. © 1990, American Chemical Society. All rights reserved.