Synthesis, Cytotoxicity, and Insight into the Mode of Action of Re(CO)₃ Thymidine Complexes

Abstract

Nucleoside analogues are extensively used in the treatment of cancer and viral diseases. The antiproliferative properties of organorhenium(I) complexes, however, have been scarcely explored to date. Herein we present the syntheses, characterization, and in vitro evaluation of Re(I)(CO)(3) core complexes of thymidine and uridine. For the binding of the Re(I)(CO)(3) core, a tridentate dipicolylamine metal chelate was introduced at positions C5', C2', N3, and C5 with spacers of various lengths. The corresponding organometallic thymidine complexes were fully characterized by IR and NMR spectroscopy and mass spectrometry. Their cytotoxicity was assessed against the A549 lung carcinoma cell line. Toxicity is dependent on the site and mode of conjugation as well as on the nature and the length of the tether. Moderate toxicity was observed for conjugates carrying the rhenium moiety at position C5' or N3 (IC(50)=124-160 microM). No toxicity was observed for complexes modified at C2' or C5. Complex 53, with a dodecylene spacer at C5', exhibits remarkable toxicity and is more potent than cisplatin, with an IC(50) value of 6.0 microM. To the best of our knowledge, this is the first report of the antiproliferative properties of [M(CO)(3)](+1)-nucleoside conjugates. In competitive inhibition experiments with A549 cell lysates and purified recombinant human thymidine kinase 1 (hTK-1), enzyme inhibition was observed for complexes modified at either N3 or C5', but our results suggest that the toxicity cannot be attributed solely to interaction with hTK-1.

Re(I) carbonyl complexes: Multimodal platforms for inorganic chemical biology

“…Other biomolecules could also be labelled and imaged, e.g. biotin [100,101], folic acid [97] or thymidine derivatives [22,51,102].…”

Underestimated Potential of Organometallic Rhenium Complexes as Anticancer Agents

“…The introduced ligands can be designed to incorporate other functional moieties such as targeting biomolecules. 28,29,34,35,39,41,44,46,47,50,51 However, the key property of the Re organometallic complexes is the possibility to prepare "hot" analogues that can be applied for radio-imaging as well as for therapy . Besides 186 Re and 188 Re isotopes, 99m Tc can often be used with the same set of ligands as the cold Re due to the similarity in the coordination chemistry of these group 7 congeners.…”

The synthesis, structure, electrochemistry and in vitro anticancer activity studies of ferrocenyl-thymine conjugates

“…Also ferrocenyl-thymine 9 and ferrocenyl-adenine 10, which were recently obtained by a "click chemistry" approach, have been tested for their antioxidant activities [33]. At this point it should be briefly mentioned that aside from ferrocenyl-nucleobase also rhenium-thymine conjugates have been recently recognized as anticancer active agents [34]. This reflect the growing importance of the entire organometallic-nucleobase conjugates family in oncology.…”