Charge dependent substrate activity of C3' and N3 functionalized, organometallic technetium and rhenium-labeled thymidine derivatives toward human thymidine kinase 1.

Détails

ID Serval
serval:BIB_73830C558D95
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Charge dependent substrate activity of C3' and N3 functionalized, organometallic technetium and rhenium-labeled thymidine derivatives toward human thymidine kinase 1.
Périodique
Bioconjugate Chemistry
Auteur(s)
Struthers Harriet, Viertl David, Kosinski Marek, Spingler Bernhard, Buchegger Franz, Schibli Roger
ISSN
1520-4812[electronic], 1043-1802[linking]
Statut éditorial
Publié
Date de publication
2010
Volume
21
Numéro
4
Pages
622-634
Langue
anglais
Résumé
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 [(18)F]3'-fluoro-3'-deoxythymidine ([(18)F]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 = (99m)Tc, Re). The click chemistry approach enabled complexes with different structures and overall charges to be 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%).
Mots-clé
Neutron-Capture Therapy, Thymidylate Synthase Inhibition, Positron-Emission-Tomography, Biological Evaluation, In-Vitro, Radiolabeled Iododeoxyuridine, Nucleoside Transporters, Deoxycytidine Kinase, Terminal Alkynes, Analogs
Pubmed
Web of science
Création de la notice
06/05/2010 16:04
Dernière modification de la notice
03/03/2018 18:19
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