Biotransformations of anticancer ruthenium(III) complexes: an X-ray absorption spectroscopic study.
An anti-metastatic drug, NAMI-A ((ImH)[Ru(III) Cl4 (Im)(dmso)]; Im=imidazole, dmso=S-bound dimethylsulfoxide), and a cytotoxic drug, KP1019 ((IndH)[Ru(III) Cl4 (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 Ru(III) . The fits point to the presence of Ru(IV/III) clusters and binding of Ru(III) 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.
School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.
Aviva
A
Levina
Jade B
JB
Aitken
Yee Yen
YY
Gwee
Zhi Jun
ZJ
Lim
Mimi
M
Liu
Anannya Mitra
AM
Singharay
Pok Fai
PF
Wong
Peter A
PA
Lay
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D056945:Hep G2 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D012428:Ruthenium / Q000737:chemistry*; D056928:X-Ray Absorption Spectroscopy
D000970:Antineoplastic Agents; D007093:Imidazoles; D009942:Organometallic Compounds; C029899:imidazole; D012428:Ruthenium; D004121:Dimethyl Sulfoxide