Organometallic Nucleosides: Synthesis and Biological Evaluation of Substituted Dicobalt Hexacarbonyl 2′‐Deoxy‐5‐oxopropynyluridines

摘要

Reactions of dicobalt octacarbonyl [Co 2 (CO) 8 ] with 2′‐deoxy‐5‐oxopropynyluridines and related compounds gave dicobalt hexacarbonyl nucleoside complexes (83–31?%). The synthetic outcomes were confirmed by X‐ray structure determination of dicobalt hexacarbonyl 2′‐deoxy‐5‐(4‐hydroxybut‐1‐yn‐1‐yl)uridine, which exhibits intermolecular hydrogen bonding between a modified base and ribose. The electronic structure of this compound was characterized by the DFT calculations. The growth inhibition of HeLa and K562 cancer cell lines by organometallic nucleosides was examined and compared to that by alkynyl nucleoside precursors. Coordination of the dicobalt carbonyl moiety to the 2′‐deoxy‐5‐alkynyluridines led to a significant increase in the cytotoxic potency. The cobalt compounds displayed antiproliferative activities with median inhibitory values (IC 50 ) in the range of 20 to 80?μ m for the HeLa cell line and 18 to 30?μ m for the K562 cell line. Coordination of an acetyl‐substituted cobalt nucleoside was expanded by using the 1,1‐bis(diphenylphosphino)methane (dppm) ligand, which exhibited cytotoxicity at comparable levels. The formation of reactive oxygen species in the presence of cobalt compounds was determined in K562 cells. The results indicate that the mechanism of action for most antiproliferative cobalt compounds may be related to the induction of oxidative stress. Stressed out : Dicobalt hexacarbonyl 5‐oxopropynyl‐2′‐deoxyuridines and a corresponding 1,1‐bis(diphenylphosphino)methane (dppm) complex are investigated. The cobalt carbonyl unit is essential to achieve a cytotoxic effect against HeLa and K562 human cancer cells in?vitro; the formation of reactive oxygen species in K562 cells indicates that the mechanism of action may be related to the induction of oxidative stress.