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Biotransformations of Anticancer Ruthenium(III) Complexes: An X-Ray Absorption Spectroscopic Study

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Abstract

An anti-metastatic drug, NAMI-A ((ImH)[RuIIICl4(Im)(dmso)]; Im=imidazole, dmso=S-bound dimethylsulfoxide), and a cytotoxic drug, KP1019 ((IndH)[RuIIICl4(Ind)2]; Ind=indazole), are two Ru-based anticancer drugs in human clinical trials. Their reactivities under biologically relevant conditions, including aqueous buffers, protein solutions or gels (e.g, albumin, transferrin and collagen), undiluted blood serum, cell-culture medium and human liver (HepG2) cancer cells, were studied by Ru K-edge X-ray absorption spectroscopy (XAS). These XAS data were fitted from linear combinations of spectra of well-characterised Ru compounds. The absence of XAS data from the parent drugs in these fits points to profound changes in the coordination environments of RuIII. The fits point to the presence of RuIV/III clusters and binding of RuIII to S-donor groups, amine/imine and carboxylato groups of proteins. Cellular uptake of KP1019 is approximately 20-fold higher than that of NAMI-A under the same conditions, but it diminishes drastically after the decomposition of KP1019 in cell-culture media, which indicate that the parent complex is taken in by cells through passive diffusion.

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