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

Abstract

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.

Lipid Nucleoside Conjugates for the Treatment of Cancer

“…In some later studies, Ryu et al developed more synthetic schemes for using diacylglycerols with different aliphatic chain lengths attached to ara-C monophosphate or ara-C diphosphate [62]. The new synthetic scheme for the synthesis of a conjugate with only one phosphate required the protection of ara-C using levulinic acid protecting groups.…”

“…Previous investigators have had many successes with phospholipid/nucleoside analog conjugates; however, there are still improvements that can be made to these compounds [59,60,[62][63][64]73]. In our laboratory, we focused on the synthesis of a thioether phospholipid (1-S-dodecyl-2-Odecyl-thioglycero-3-phosphatidic acid) conjugated to either gemcitabine or ara-C [75].…”

Synthesis of Cytarabine Lipid Drug Conjugate for Treatment of Meningeal Leukemia: Development, Characterization and <I>In</I> <I>Vitro</I> Cell Line Studies

“…Several independent researchers have also tried to address these drawbacks of Cyt by synthesizing its various prodrugs, [26][27][28][29] analogues 30 and conjugates. [31][32][33][34][35][36][37] Phospholipid-Ara-C conjugates were prepared as a prodrug of Cyt and found to be much more effective than Ara-C in vivo. 31 Conjugate of thioether phospholipid with Cyt showed stability in a micellar solution and offered substantial therapeutic benefit to mice with leukemia.…”

“…[31][32][33][34][35][36][37] Phospholipid-Ara-C conjugates were prepared as a prodrug of Cyt and found to be much more effective than Ara-C in vivo. 31 Conjugate of thioether phospholipid with Cyt showed stability in a micellar solution and offered substantial therapeutic benefit to mice with leukemia. 32 Fatty acyl derivatives of Cyt were developed to improve cellular uptake.…”

A comparison of enzymatic phosphorylation and phosphatidylation of β-l- and β-d-nucleosides

“…These drawbacks of nucleoside therapeutics provoke a profound interest in the search of prodrugs exhibiting an effectiveness superior to that of the parent drug. Among such derivatives, conjugates of nucleosides and phospholipids attracted attention and it was demonstrated that these derivatives display advantageous biological properties over free nucleosides (Ryu et al 1982;Shuto et al 1995;Vodovozova et al 1996;Herrmann et al 1997;Brachwitz et al 1998Brachwitz et al , 1999Kucera et al 1998;Mavromoustakos et al 2001;Alexander et al 2003; for a review, see Morris-Natschke et al 2003).…”