Synthesis, in vitro and in silico assessment of organometallic Rhenium(I) and Technetium(I) thymidine complexes

• Published in: Journal of organometallic chemistry Vol. 692; no. 6; pp. 1255 - 1264
• Main Authors: Stichelberger, M., Desbouis, D., Spiwok, V., Scapozza, L., Schubiger, P.A., Schibli, R.
• Format: Journal Article
• Language: English
• Published: LAUSANNE Elsevier B.V 15.02.2007; Elsevier
• Subjects: Chemistry; Chemistry, Inorganic & Nuclear; Chemistry, Organic; Enzyme inhibitors; Physical Sciences; Rhenium; Science & Technology; Technetium; Technetium; Enzyme inhibitors; Rhenium; REPLICATION; THERAPY; RADIOPHARMACEUTICALS; KINASE; POTENTIAL IMPACT; INHIBITORS; enzyme inhibitors; CANCER
• ISSN: 0022-328X; 1872-8561
• DOI: 10.1016/j.jorganchem.2006.08.101

Organometallic technetium and rhenium complexes of 5′-amino-5′-deoxythymidine derivatives were synthesized. Enzyme kinetic studies revealed mixed (uncompetitive) inhibition of human TK for all complexes. The complex with a spatial separation of the thymidine and the metal entities by ∼30 Å revealed competitive inhibition of HSV1 TK. Molecular dynamic calculations confirmed these experimental findings. Thymidine kinases have been identified as suitable targets for non-invasive imaging of gene therapy and cancer. Thus, there is a high interest in new, reliable and inexpensive radiolabeled thymidine analogues for these applications. In this study we present the synthesis and in vitro evaluation of M(CO) 3-complexes of thymidine (M = 99mTc, Re) for potential use in SPECT tumor imaging. 5′-amino-5′-deoxythymidine was derivatized at position C5′ with spacers of various lengths (∼0–30 Å) carrying tridentate metal chelating entities such as iminodiacetic acid and picolylamine- N-monoacetic acid. The nucleoside derivatives were reacted with the precursors [ReBr 3(CO) 3] 2− and [ 99mTc(OH 2) 3(CO) 3] +, respectively. The organometallic thymidine complexes have been fully characterized by means of IR, NMR and mass spectrometry. Enzyme kinetic studies revealed mixed inhibition of the human cytosolic thymidine kinase with K i values ranging from 4.4 to 334 μM for all thymidine complexes. Competitive inhibition of herpes simplex virus type 1 thymidine kinase was only achieved when thymidine and the metal core were separated by a spacer of approximately 30 Å length. These findings were supported by in silico molecular docking and molecular dynamic experiments.