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Synthesis, Biological Evaluation, and Radioiodination of Halogenated closo-Carboranylthymidine Analogues
Faculty
Science
Year:
2012
Type of Publication:
Article
Pages:
629-639
Authors:
Tiwari, Rohit, Agarwal, Hitesh K, Khalil, Ahmed, Goudah, Ayman, Barth, Rolf F, Tjarks, Werner, Toppino, Antonio, Huo, Tianyao, Byun, Youngjoo, Gallucci, Judith, Hasabenaby, Sherifa, Baiocchi, Robert A, Darby, Michael V
DOI:
10.1021/ic202150b
Journal:
INORGANIC CHEMISTRY AMER CHEMICAL SOC
Volume:
51
Research Area:
Chemistry
ISSN
ISI:000298712000079
Keywords :
Synthesis, Biological Evaluation, , Radioiodination , Halogenated closo-Carboranylthymidine
Abstract:
The synthesis and initial biological evaluation of 3-carboranylthymidine analogues (3CTAs) that are (radio)halogenated at the closo-carborane cluster are described. Radiohalogenated 3CTAs have the potential to be used in the radiotherapy and imaging of cancer because they may be selectively entrapped in tumor cells through monophosphorylation by human thymidine kinase 1 (hTK1). Two strategies for the synthesis of a I-127-labeled form of a specific 3CTA, previously designated as N5, are described: (1) direct iodination of N5 with iodine monochloride and aluminum chloride to obtain N5-I-127 and (2) initial monoiodination of o-carborane to 9-iodo-o-carborane followed by its functionalization to N5-I-127. The former strategy produced N5-I-127 in low yields along with di-, tri-, and tetraiodinated N5 as well as decomposition products, whereas the latter method produced only N5-I-127 in high yields. N5-I-127 was subjected to nudeophilic halogen- and isotope-exchange reactions using Na-79/Br-81 and (NaI)-I-125, respectively, in the presence of Herrmann's catalyst to obtain N5-(79)/Br-81 and N5-I-125, respectively. Two intermediate products formed using the second strategy, 1-(tert-butyldimethylsilyl)-9-iodo-o-carborane and 1-(tert-butyldimethylsilyl)-12-iodo-o-carborane, were subjected to X-ray diffraction studies to confirm that substitution at a single carbon atom of 9-iodo-o-carborane resulted in the formation of two structural isomers. To the best of our knowledge, this is the first report of halogen- and isotope-exchange reactions of B-halocarboranes that have been conjugated to a complex biomolecule. Human TK1 phosphorylation rates of NS, N5-I-127, and N5-(79)/Br-81 ranged from 38.0\% to 29.6\% relative to that of thymidine, the endogenous hTK1 substrate. The in vitro uptake of NS, N5-I-127, and NS-(79)/Br-81 in L929 TK1(+) cells was 2.0, 1.8, and 1.4 times greater than that in L929 TK1() cells.
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