X-ray Structure Analysis of Indazolium trans-[Tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) Bound to Human Serum Albumin Reveals Two Ruthenium Binding Sites and Provides Insights into the Drug Binding Mechanism

Abstract

Ruthenium(III) complexes are promising candidates for anticancer drugs, especially the clinically studied indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019) and its analogue sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (NKP-1339). Several studies have emphasized the likely role of human serum proteins in the transportation and accumulation of ruthenium(III) complexes in tumors. Therefore, the interaction between KP1019 and human serum albumin was investigated by means of X-ray crystallography and inductively coupled plasma mass spectrometry (ICP-MS). The structural data unambiguously reveal the binding of two ruthenium atoms to histidine residues 146 and 242, which are both located within well-known hydrophobic binding pockets of albumin. The ruthenium centers are octahedrally coordinated by solvent molecules revealing the dissociation of both indazole ligands from the ruthenium-based drug. However, a binding mechanism is proposed indicating the importance of the indazole ligands for binding site recognition and thus their indispensable role for the binding of KP1019.

Encapsulation of the Dinuclear Trithiolato‐Bridged Arene Ruthenium Complex Diruthenium‐1 in an Apoferritin Nanocage: Structure and Cytotoxicity

“…To further confirm the presence of Ru atoms within the crystals of DiRu‐1‐encapsulated AFt, ICP‐MS measurements were performed. Similar experiments were performed by Rompel and co‐workers to verify the presence of KP1019 in human serum albumin–KP1019 crystals and also suggested in recent protocols for the determination of the X‐ray structures of the adducts formed in the reaction between proteins and metallodrugs . Crystals of AFt and of DiRu‐1‐encapsulated AFt were extensively washed with the reservoir solution and then dissolved in 20 μL of milli‐Q water.…”

RuIII Complexes for Anticancer Therapy: The Importance of Being Nucleolipidic

“…Biological tests [21,39,72] showed that KP1019 is highly active against colorectal cancer cell lines both in vitro and in vivo. [77] In addition, both of these Ru III complexes readily react with biological reductants, [70] suggesting that the in situ reduction of Ru III to Ru II [14] species may be relevant for their biological activity, [18,25,60] producing a more reactive form [14,71] able to interact with proteins [59,65,[78][79][80] and/ or to bind nucleic acids. [39] KP1019 is more readily taken up by cancer cells than NAMI-A and is more stable toward hydrolysis, [18,56,63,72,73] although this is a pH-dependent process, proceeding more rapidly at higher pH.…”

Electronic State of Sodium trans-[Tetrachloridobis(1H-indazole)ruthenate(III)] (NKP-1339) in Tumor, Liver and Kidney Tissue of a SW480-bearing Mouse

“…The chlorido donors bound to Ru in the metabolites do not necessarily need to come from the parent drug as they can be the result of ligand-exchange reactions with the medium. Ligand exchange has recently been supported by X-ray structure studies41 of the highly similar KP1019 bound to human serum albumin, one of the most likely transport proteins4243. Two octahedral Ru sites were found with first shell N donor atoms arising from the amino acids (Ru1: His146; Ru2: Lys199 and His242)41.…”