Synthesis, biological evaluation, and radioiodination of halogenated closo -carboranylthymidine analogues(1)

Rohit Tiwari, Antonio Toppino, Hitesh K. Agarwal, Tianyao Huo, Youngjoo Byun, Judith Gallucci, Sherifa Hasabelnaby, Ahmed Khalil, Ayman Goudah, Robert A. Baiocchi, Michael V. Darby, Rolf F. Barth, Werner Tjarks

Research output: Contribution to journalArticle

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 127I-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- 127I and (2) initial monoiodination of o-carborane to 9-iodo-o-carborane followed by its functionalization to N5- 127I. The former strategy produced N5- 127I in low yields along with di-, tri-, and tetraiodinated N5 as well as decomposition products, whereas the latter method produced only N5- 127I in high yields. N5- 127I was subjected to nucleophilic halogen- and isotope-exchange reactions using Na 79/81Br and Na 125I, respectively, in the presence of Herrmann's catalyst to obtain N5- 79/81Br and N5- 125I, 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 N5, N5- 127I, and N5- 79/81Br ranged from 38.0% to 29.6% relative to that of thymidine, the endogenous hTK1 substrate. The in vitro uptake of N5, N5- 127I, and N5- 79/81Br in L929 TK1(+) cells was 2.0, 1.8, and 1.4 times greater than that in L929 TK1(-) cells.

Original languageEnglish (US)
Pages (from-to)629-639
Number of pages11
JournalInorganic Chemistry
Volume51
Issue number1
DOIs
StatePublished - Jan 2 2012
Externally publishedYes

ASJC Scopus subject areas

  • Inorganic Chemistry
  • Physical and Theoretical Chemistry

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    Tiwari, R., Toppino, A., Agarwal, H. K., Huo, T., Byun, Y., Gallucci, J., Hasabelnaby, S., Khalil, A., Goudah, A., Baiocchi, R. A., Darby, M. V., Barth, R. F., & Tjarks, W. (2012). Synthesis, biological evaluation, and radioiodination of halogenated closo -carboranylthymidine analogues(1). Inorganic Chemistry, 51(1), 629-639. https://doi.org/10.1021/ic202150b