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.
Highlights
Metal complexes have a broad range of medical applications and are extensively used in the treatment of cancer
There are abundant reports about Ru complexes with remarkable antiproliferative properties, which enrich the field of drug development; the most prominent ones are the Ru(III)-based anticancer drugs indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (1, KP1019),[15] its sodium salt analogue sodium trans[tetrachlorobis(1H-indazole)ruthenate(III)] (2, NKP-1339)[16] (Figure 1), and the new antimetastasis inhibitor imidazolium trans-[tetrachlorobis(1H-imidazole)(S-dimethyl sulfoxide)ruthenate(III)] (NAMI-A)[17] (Figure S1), though the clinical development of the last one seems to have come to a halt.[18]
The structure of the HSA−Myr−1 complex reported here reveals the binding of two Ru moieties, which is independently confirmed by inductively coupled plasma mass spectrometry (ICP-MS) measurements
Summary
Metal complexes have a broad range of medical applications and are extensively used in the treatment of cancer. After the binding site is reached, the heterocyclic ligands are dissociated after a certain amount of time (∼24 h in the soaking experiment) so that the Ru(III) center is able to coordinate to the protein under ligand-exchange with protein-derived His ligands This is possible because the imidazole groups of the His represent stronger donors toward Ru than the indazole ligands, leading to a more stable Ru−N bond.[58] Cetinbas et al.[38] suggested a similar two-step reaction pathway before, describing an initially rapid noncovalent binding of 1 to HSA followed by slow covalent binding. Article of both Ru centers and the need for large and hydrophobic binding pockets for enhanced bioavailability and cytotoxicity
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