Organometallic [Re(CO)3]+ and [Re(CO)2(NO)]2+ labeled substrates for human thymidine kinase 1.
Thymidine was functionalized at position N3 with a tridentate iminodiacetic acid chelating system and a potentially tetradentate mercaptoethyliminodiacetic acid chelating system. Spacers of different lengths (ethyl and butyl) were introduced between the chelators and thymidine. The derivatives were labeled with the [Re(CO)(2)(NO)](2+) and [Re(CO)(3)](+) cores to give isostructural complexes with different overall charges. All complexes were analyzed by NMR, MS, and IR, and in addition, the X-ray structure of a [Re(CO)(2)(NO)](2+) labeled thymidine derivative functionalized at the N3 position was solved. The ligands incorporating the potentially tetradentate mercaptoethyliminodiacetic acid chelating system coordinated tridentately through iminodiacetic acid to both the [Re(CO)(2)(NO)](2+) core and the [Re(CO)(3)](+) core. This was surprising given that the reaction of [NEt(4)][Re(CO)(2)(NO)Br(3)] with the model ligand ethylmercaptoethyliminodiacetic acid led to dissociation of a carbonyl ligand and formation of a monocarbonyl-mononitrosyl complex, as confirmed by X-ray structure analysis. All of the organometallic thymidine derivatives were substrates for human thymidine kinase 1, a key enzyme in (cancer) cell proliferation. Neutral [Re(CO)(2)(NO)](2+) labeled thymidine derivatives revealed substrate activity ranging from 24 to 40%, and the structurally analogous anionic [Re(CO)(3)](+) labeled thymidine derivatives from 20 to 38% compared with the natural substrate thymidine.
Struthers
Harriet
H
Department of Chemistry and Applied Biosciences ETH Zurich, 8093 Zurich, Switzerland.
Hagenbach
Adelheid
A
Abram
Ulrich
U
Schibli
Roger
R
D019342:Acetic Acid / Q000737:chemistry; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000737:chemistry*; D012211:Rhenium / Q000737:chemistry*; D013057:Spectrum Analysis; D013194:Staining and Labeling; D013936:Thymidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D013937:Thymidine Kinase / Q000378:metabolism*; D014867:Water / Q000737:chemistry
D008024:Ligands; D009942:Organometallic Compounds; D014867:Water; D012211:Rhenium; D013937:Thymidine Kinase; C092717:thymidine kinase 1; D019342:Acetic Acid; D013936:Thymidine