Phospholipid-nucleoside conjugates. 3. Syntheses and preliminary biological evaluation of 1-beta-D-arabinofuranosylcytosine 5'-monophosphate-L-1,2-dipalmitin and selected 1-beta-D-arabinofuranosylcytosine 5-diphosphate-L-1,2-diacylglycerols.

Several new phospholipid-ara-C conjugates have been prepared and tested as prodrugs of the parent ara-C. The new derivative include ara-CMP-L-dipalmitin, ara-CDP-L-distearin, ara-CDP-L dimyristin, ara-CDP-L-diolein, and the radioactively labeled derivative ara-CDP-L-di[1-14C]palmitin. In addition, the unusually stable ara-CMP-L-dipalmitin-N-phosphoryldicyclohexylurea adduct was isolated as a crystalline solid (two diastereomers) in the reaction sequence to prepare ara-CMP-L-dipalmitin. The new prodrugs were solubilized by sonication methods and tested for their antiproliferative activity in vitro against mouse myeloma MPC-11 cells and against L1210 lymphoid leukemia. Such studies demonstrated that the antiproliferative activities of the prodrugs (as determined by ED50) were less that ara-C on a molar basis. In the mouse myeloma cell line some evidence was obtained that the antiproliferative activity was related to the chain length of the fatty acid side chains in the prodrugs. In in vivo studies against L1210 lymphoid leukemia in mice, the prodrugs were shown to be much more effective than ara-C, with the overall efficacy apparently being independent of the length of the fatty acid side chain. Some evidence was obtained in the vivo studies that the ara-CDP-L-dimyristin, which bears the shortest fatty acid side chain, was more toxic at the higher dosages than the longer chain length derivatives.