Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-44991
Struthers, H; Viertl, D; Kosinski, M; Spingler, B; Buchegger, F; Schibli, R (2010). Charge dependent substrate activity of C3' and N3 functionalized, organometallic Technetium and Rhenium-labeled thymidine derivatives toward human thymidine kinase 1. Bioconjugate Chemistry, 21(4):622-634.
Human cytosolic thymidine kinase (hTK1) has proven to be a suitable target for the noninvasive imaging of cancer cell proliferation using radiolabeled thymidine analogues such as F-18]3'-fluoro-3'-deoxythymidine (F-18]FLT). A thymidine analogue for single photon emission computed tomography (SPECT), which incorporates the readily available and inexpensive nuclide technetium-99m, would be of considerable practical interest. hTK1 is known to accommodate modification of the structure of the natural substrate thymidine at the positions N3 and C3' and, to a lesser extent, C5. In this work, we used the copper-catalyzed azide-alkyne cycloaddition to synthesize two series of derivatives in which thymidine is functionalized at either the C3' or N3 position with chelating systems suitable for the M(CO)(3) core (M = Tc-99m, Re). The click chemistry approach enabled complexes with different structures and overall charges to he synthesized from a common precursor. Using this strategy, the first organometallic hTK1 substrates in which thymidine is modified at the C3' position were identified. Phosphorylation of the organometallic derivatives was measured relative to thymidine. We have shown that the influence of the overall charge of the derivatives is dependent on the position of functionalization. In the case of the C3'-functionalized derivatives, neutral and anionic substrates were most readily phosphorylated (20-28% of the value for the parent ligand thymidine), whereas for the N3-functionalized derivatives, cationic and neutral complexes were apparently better substrates for the enzyme (14-18%) than anionic derivatives (9%).
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||07 Faculty of Science > Department of Chemistry|
|Deposited On:||08 Feb 2011 14:24|
|Last Modified:||03 Dec 2013 03:33|
|Publisher:||American Chemical Society|
|Additional Information:||This document is the Accepted Manuscript version of a Published Work that appeared in final form in Bioconjugate Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/bc900380n|
|Other Identification Number:||ISI:000276817800009|
|Citations:||Web of Science®. Times Cited: 10|
Scopus®. Citation Count: 11
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