NUCLEOSIDE CONJUGATES .14. SYNTHESIS AND ANTITUMOR-ACTIVITY OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE CONJUGATES OF ETHER LIPIDS WITH IMPROVED WATER SOLUBILITY

A series of ara-CDP-rac-1-O-alkyl-2-O-acylglycerol (9a-f), analogues o f highly active ara-CDP-rac-1-O-hexadecyl-2-O-palmitoylglycerol (1) an d Cytoros(2) (2), was prepared, and solubility, lipophilicity, and str ucture-activity relationships of these conjugates were investigated. C onjugates 9a-f containing sn-1 alkyl (<C-16) and sn-2 fatty acyl (<C-1 4) and sn-1 alkyl (<C-14) and sn-2 fatty acyl (<C-16) substituents of the glycerol were water-soluble by shaking, while those with the sn-1 alkyl (>C-16) and the sn-2 fatty acyl (>C-16) such as conjugate 1 were sparingly soluble. Conjugates 9a-c,e were almost completely solubiliz ed in water by shaking. However, a large portion of conjugates 9d and 9f in water by shaking exist in micelles with mean diameters ranging 7 .0-55.2 nm. The partition coefficients (1-octanol/PBS) of the water-so luble conjugates were about 9-18 times greater than that of ara-C. A s ingle dose (300 mg/kg) of conjugates 9d and 9f produced a significant increase in life span (ILS 206 to >543%) with 17-67% long-term survivo rs (>45 days) in mice bearing ip-implanted L1210 lymphoid leukemia. Th ese results were comparable to those of the previous conjugate 1 and C ytoros (2). In contrast, conjugates 9a-c,e at single doses were less e ffective (ILS 69-178% with no long-term survivors). However, two (qd, 1, 7) or three (qd 1, 5, 9) divided doses of these conjugates were fou nd to be as effective as a single dose of the previous conjugates. The three divided doses (150 mg/kg per day) of conjugates 9d, 9e, and 9f produced a remarkable antitumor activity in L1210 leukemic mice (ILS > 350% with >50% long-term survivors). Because of the convenient formula tion and the significant antitumor activities, the water-soluble conju gates 9d, 9e, and 9f warrant further investigation.