title: Synthesis, biological evaluation, and radioiodination of halogenated closo-carboranylthymidine analogues.
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 (127)I-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-(127)I and (2) initial monoiodination of o-carborane to 9-iodo-o-carborane followed by its functionalization to N5-(127)I. The former strategy produced N5-(127)I in low yields along with di-, tri-, and tetraiodinated N5 as well as decomposition products, whereas the latter method produced only N5-(127)I in high yields. N5-(127)I was subjected to nucleophilic halogen- and isotope-exchange reactions using Na(79/81)Br and Na(125)I, respectively, in the presence of Herrmann's catalyst to obtain N5-(79/81)Br and N5-(125)I, 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-(127)I, and N5-(79/81)Br ranged from 38.0% to 29.6% relative to that of thymidine, the endogenous hTK1 substrate. The in vitro uptake of N5, N5-(127)I, and N5-(79/81)Br in L929 TK1(+) cells was 2.0, 1.8, and 1.4 times greater than that in L929 TK1(-) cells.
authors.affiliation: Division of Medicinal Chemistry & Pharmacognosy, The Ohio State University, 500 West 12th Avenue, Columbus, Ohio 43210, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Tiwari
authors.forename: Antonio
authors.initials: A
authors.lastname: Toppino
authors.forename: Hitesh K
authors.initials: HK
authors.lastname: Agarwal
authors.forename: Tianyao
authors.initials: T
authors.lastname: Huo
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Byun
authors.forename: Judith
authors.initials: J
authors.lastname: Gallucci
authors.forename: Sherifa
authors.initials: S
authors.lastname: Hasabelnaby
authors.forename: Ahmed
authors.initials: A
authors.lastname: Khalil
authors.forename: Ayman
authors.initials: A
authors.lastname: Goudah
authors.forename: Robert A
authors.initials: RA
authors.lastname: Baiocchi
authors.forename: Michael V
authors.initials: MV
authors.lastname: Darby
authors.forename: Rolf F
authors.initials: RF
authors.lastname: Barth
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
mesh_terms: D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D054879:Halogenation; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D013936:Thymidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013937:Thymidine Kinase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D007457:Iodine Radioisotopes; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D013936:Thymidine