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Preparation and biological evaluation of 10B-enriched 3-[5-{2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH), a new boron delivery agent for boron neutron capture therapy of brain tumors.

Byun Y, Thirumamagal BT, Yang W, Eriksson S, Barth RF, Tjarks W

Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University, Columbus, OH, USA. byun.12@osu.edu

3-[5-{2-(2,3-Dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (compound 1, N5-2OH) belongs to a novel class of boron delivery agents for neutron capture therapy, which was designated 3-carboranylthymidine analogue (3CTAs). Two shorter and more convenient synthetic routes were developed for the synthesis of 1 in the 10B-enriched form, which is necessary for its preclinical and clinical evaluation in neutron irradiation studies. For more insight on structure-activity relationships, various stereochemical and geometrical isomers of 1 were synthesized and their specificities as substrate for human thymidine kinase 1 (hTK1) were evaluated. A computational model for the binding of various isomers of 1 to the active site of hTK1 was developed. Preliminary studies carried out in F98 glioma bearing rats that had received a 10B-enriched form of 1 followed by neutron irradiation demonstrated a significant prolongation in survival times compared to control animals, suggesting that further studies are warranted to evaluate the therapeutic potential of 1.

Published 31 August 2006 in J Med Chem, 49(18): 5513-23.
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