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-acylglycerols (9a-f), analogues of highly active ara-CDP-rac-1-O-hexadecyl-2-O-palmitoylglycerol (1) and Cytoros2 (2), was prepared, and solubility, lipophilicity, and structure-activity relationships of these conjugates were investigated. Conjugates 9a-f containing sn-1 alkyl (< C16) and sn-2 fatty acyl (< C14) and sn-1 alkyl (< C14) and sn-2 fatty acyl (< C16) substituents of the glycerol were water-soluble by shaking, while those with the sn-1 alkyl (> C16) and the sn-2 fatty acyl (> C16) such as conjugate 1 were sparingly soluble. Conjugates 9a-c,e were almost completely solubilized 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-soluble conjugates were about 9-18 times greater than that of ara-C. A single 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 survivors (> 45 days) in mice bearing ip-implanted L1210 lymphoid leukemia. These results were comparable to those of the previous conjugate 1 and Cytoros (2). In contrast, conjugates 9a-c,e at single doses were less effective (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 found 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 formulation and the significant antitumor activities, the water-soluble conjugates 9d, 9e, and 9f warrant further investigation.