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.
Yan
Junhua
J
College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
Naeslund
Charlotta
C
Al-Madhoun
Ashraf S
AS
Wang
Jianghai
J
Ji
Weihua
W
Cosquer
Guirec Y
GY
Johnsamuel
Jayaseharan
J
Sjöberg
Stefan
S
Eriksson
Staffan
S
Tjarks
Werner
W
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