Phospholipid derivatives of cladribine and fludarabine: synthesis and biological properties

Phospholipid derivatives of Anticancer nucleosides cladribine and fludarabine (F-ara-A) bearing 1,2- and 1,3-diacylglycerol moieties have been prepared by the H-phosphonate approach using 1,1,3,3-tetraisopropyldisiloxane-1,3-diyl protecting group for cladribine and a combination of tert-butyldimethylsilyl and levulinyl protecting groups for 2-fluoroadenine nucleosides. The synthesized conjugates exhibited lower in vitro antiproliferative activity against human tumor cell lines in comparison with the same concentrations of the parent cladribine and fludarabine phosphate. In the course of biokinetic study, it was found that intragastric administration of phospholipid F-ara-A derivatives to Wistar rats and ICR outbred male mice led to a slow release of F-ara-A into the bloodstream, a smooth increase in nucleoside concentration, and prolonged serum circulation of liberated nucleoside. The oral bioavailability of F-ara-A from 1,2-dimyristoylglycerophosphate derivative 29 was similar to its oral bioavailability from fludarabine phosphate.

1,2-, 1,3-Diacylglycerophospholipids; Antiproliferative activity; Cladribine; Fludarabine; Pharmacokinetic properties; Prodrugs.