Synthesis and biological evaluation of 3'-carboranyl thymidine analogues.
Boron neutron capture therapy (BNCT) is a chemoradio-therapeutic method for the treatment of cancer. It depends on the selective targeting of tumor cells by boron-containing compounds. One category of BNCT agents with potential to selectively target tumor cells may be thymidine derivatives substituted at the 3'-position with appropriate boron moieties. Thus, several thymidine analogues were synthesized with a carborane cluster bound to the 3'-position either through an ether or a carbon linkage. The latter are the first reported carborane-containing nucleosides in which the carboranyl entity is directly linked to the carbohydrate portion of the nucleoside by a carbon-carbon bond. Low but significant phosphorylation rates in the range of 0.18% that of thymidine were observed for the carbon-linked 3'-carboranyl thymidine analogues in phosphoryl transfer assays using recombinant preparations of thymidine kinases 1 (TK1) and thymidine kinases 2 (TK2). Some of the ether-linked 3'-carboranyl thymidine analogues appeared to be slightly unstable under acidic as well as phosphoryl transfer assay conditions and were, if at all, poor substrates for TK1.
College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
Junhua
J
Yan
Charlotta
C
Naeslund
Ashraf S
AS
Al-Madhoun
Jianghai
J
Wang
Weihua
W
Ji
Guirec Y
GY
Cosquer
Jayaseharan
J
Johnsamuel
Stefan
S
Sjöberg
Staffan
S
Eriksson
Werner
W
Tjarks
D001896:Boron Compounds / Q000737:chemistry*; D016754:Boron Neutron Capture Therapy; D015195:Drug Design; D015394:Molecular Structure; D010766:Phosphorylation; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000378:metabolism
D001896:Boron Compounds; D013937:Thymidine Kinase; D013936:Thymidine