Synthesis, structures and hypoxia-selective cytotoxicity of cobalt(III) complexes containing tridentate amine and nitrogen mustardligands

Abstract

Cobalt(III) complexes containing the tridentate nitrogen mustard ligand N,N-bis(2-chloroethyl)diethylenetriamine (DCD) and the non-alkylating analogs N,N-diethyldiethylenetriamine (DED) and diethylenetriamine (dien) have been synthesised and the mustard complexes evaluated as potential hypoxia-selective anticancer drugs. The complexes were prepared from the precursor trans-K₂[Co(acac)(CO₃)(NO₂)₂]·H₂O in a charcoal-catalyzed substitution reaction. Reaction of this precursor with dien·3HCl in water resulted in the isolation of two isomeric products, mer- and s-fac-[Co(dien)(acac)(NO₂)]⁺. Reaction in methanol with DED·3HCl gave one product, mer-[Co(DED)(acac)(NO₂)]ClO₄, while from the reaction with DCD·3HCl both the tridentate mustard complex mer-[Co(DCD)(acac)(NO₂)]ClO₄ and, in low yield, a complex containing DCD coordinated in a bidentate fashion, trans-Co(η²-DCD)(acac)(NO₂)₂, were isolated. The two DCD complexes were characterized by X-ray structure determinations, which confirm the tridentate coordination with a long cobalt–tertiary nitrogen bond distance in the former, and bidentate coordination with the mustard nitrogen as a pendant arm in the latter. The bidentate complex, which contains a free nitrogen mustard, had cytotoxicity similar to that of the free ligand, but cytotoxicity was successfully masked in the tridentate complex, which showed modest hypoxic selectivity (five-fold) in a clonogenic assay.