Organometallic [Re(CO)₃]⁺ and [Re(CO)₂(NO)]²⁺ Labeled Substrates for Human Thymidine Kinase 1

Abstract

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 [NEt4][Re(CO)2(NO)Br3] 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