NUCLEOSIDE CONJUGATES .13. SYNTHESIS AND ANTITUMOR-ACTIVITY OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE CONJUGATES OF THIOETHER LIPIDS WITH IMPROVED WATER SOLUBILITY

A series of ara-CDP-rac-1-S-alkyl-2-0-acyl-1-thioglycerols (3-12), ana logues of highly active Cytoros2 (1), was prepared, and solubility, li pophilicity, and structure-activity relationships of these conjugates were investigated. The conjugates with sn-1 alkyl (<C18) and sn-2 fatt y acyl (<C14) substituents of the thioglycerol were water-soluble, whi le those with the sn-1 alkyl (>C14) and the sn-2 fatty acyl (>C16) wer e sparingly soluble. The latter formed micelles upon sonication. Conju gate 7 containing the sn-1 tetradecyl and the sn-2 palmitoyl (C16) gro ups formed micelles by both sonication and shaking. The partition coef ficients (1-octanol/PBS) of the water-soluble conjugates were about 20 times greater than that of ara-C. The water-insoluble showed a more t han 40 times increase. A single dose of the micelle-forming conjugates 7 and 10 produced a significant increase in life span (ILS >421 %) wi th 50 % long-term survivors (>45 days) in mice bearing ip-implanted L1 210 lymphoid leukemia. These results were comparable to those of previ ous micelle-forming conjugate 1 (Cytoros). In contrast, the water-solu ble conjugates at single doses were less effective (ILS 81-386% with 0 -33% long-term survivors). However, three divided doses of the water-s oluble conjugates were found to be as effective as a single dose of mi cellar solution of the water-insoluble. The results indicate that conj ugate 7 and most of the water-soluble derivatives warrant further inve stigation.