title: Phospholipid derivatives of cladribine and fludarabine: synthesis and biological properties.
abstract: 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.
authors.affiliation: Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, BY-220141 Minsk, Belarus. Electronic address: ilonaolenikova@tut.by.
authors.forename: Ilona
authors.initials: I
authors.lastname: Tsybulskaya
authors.affiliation: Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, BY-220141 Minsk, Belarus.
authors.forename: Tamara
authors.initials: T
authors.lastname: Kulak
authors.affiliation: Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, BY-220141 Minsk, Belarus.
authors.forename: Elena
authors.initials: E
authors.lastname: Kalinichenko
authors.affiliation: Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, BY-220141 Minsk, Belarus.
authors.forename: Alexander
authors.initials: A
authors.lastname: Baranovsky
authors.affiliation: Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, BY-220141 Minsk, Belarus.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bogushevich
authors.affiliation: Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, BY-220141 Minsk, Belarus.
authors.forename: Marina
authors.initials: M
authors.lastname: Golubeva
authors.affiliation: Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus, BY-220141 Minsk, Belarus.
authors.forename: Boleslav
authors.initials: B
authors.lastname: Kuzmitsky
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D001682:Biological Availability; D001711:Biotransformation; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D017338:Cladribine / Q000031:analogs & derivatives / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004075:Diglycerides / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D063065:Organophosphonates / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism; D011355:Prodrugs; D051381:Rats; D017208:Rats, Wistar; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000493:pharmacokinetics
chemical_list: D000964:Antimetabolites, Antineoplastic; D004075:Diglycerides; D063065:Organophosphonates; D010743:Phospholipids; D011355:Prodrugs; D017338:Cladribine; D014740:Vidarabine; C024352:fludarabine
keywords: 1,2-, 1,3-Diacylglycerophospholipids; Antiproliferative activity; Cladribine; Fludarabine; Pharmacokinetic properties; Prodrugs