Nucleoside Conjugates. 14. Synthesis and Antitumor Activity of 1-β-D-Arabinofuranosylcytosine Conjugates of Ether Lipids with Improved Water Solubility

Article abstract of DOI:10.1021/jm00010a006

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 Cytoros (2), was prepared, and solubility, lipophilicity, and structure-activity relationships of these conjugates were investigated.Conjugates 9a-f containing 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 >543percent) with 17-67percent 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 69-178percent 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 >350percent with >50percent long-term servivors).Because of the convenient formulation and the significant antitumor activities, the water-soluble conjugates 9d, 9e, and 9f warrant further investigation.