Methionine Binding to Dirhodium(II) Tetraacetate

Abstract

The reaction between antitumor active dirhodium(II) tetraacetate and DL-methionine (HMet) was followed in aqueous solution and showed initially mixtures of 1:1 and 1:2 adducts [Rh2(AcO)4(HMet)(H2O)] (AcO− = CH3COO−) and [Rh2(AcO)4(HMet)2] formed at room temperature (RT), as evidenced by UV-vis spectroscopy and electrospray ionization mass spectrometry (ESI-MS). Rh K-edge extended X-ray absorption fine structure (EXAFS) spectroscopy confirmed methionine thioether binding to the axial positions of the Rh2(AcO)4 cage structure. With excess HMet at RT stepwise displacement of the acetate groups was observed after some time using ESI-MS. Heating the solution to 40° for 24 h accelerated the substitution reaction leading to stable dirhodium(II) species with two acetate ligands displaced by two methionine groups. The crystal structure of the purple [RhII2(AcO)2(D-Met)(L-Met)]·6H2O compound obtained from the solution revealed tridentate coordination of the methionine ligands to the Rh(II) ions, with the thioether S atoms in equatorial positions. A minor amount of a light orange monomeric [RhIII(Met)2](AcO) complex also formed in the solution was isolated by size exclusion chromatography, and identified by ESI-MS. Crystals of [RhIII(D-Met)(L-Met)]Cl·3H2O were prepared by reacting RhCl3 and DL-HMet. The crystal structure showed tridentate binding of the methionine ligands to the Rh(III) ion in a trans-S,N,O arrangement.

Unusual Structural Features in the Adduct of Dirhodium Tetraacetate with Lysozyme

“…In this structure, the Rh(III) distance is 3.18 ± 0.02 Å. This distance is similar to that previously found for the aerobic reaction product from aqueous solutions of Rh 2 (O 2 CCH 3 ) 4 and glutathione and in agreement with EXAFS data [ 22 , 49 ]. Thus, it seems that in our structure the acetate and the carboxylate C-terminal tails of the two symmetry-related molecules can bridge two metal centers acting as the sulfur atoms in the Rh(III)–S–Rh(III) unit found in the product of the reaction with sodium thiolate [ 49 ].…”

“…In solution studies demonstrated that dirhodium carboxylate compounds are able to bind proteins [ 12 , 22 , 23 , 26 , 28 , 29 ]. However, there are only very scarce structural information on this interaction.…”

“…Due to their possible role in the definition of the mechanism of action of these potential anticancer agents, the interactions of [Rh 2 (μ-O 2 CCH 3 ) 4 ] with amino acids, peptides, and proteins have been studied, but contrasting results have been reported in the literature [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Reaction of [Rh 2 (μ-O 2 CCH 3 ) 4 ] with Cys and its derivatives and with glutathione leads to oxidation of the Rh(II)–Rh(II) dimeric unit and formation of Rh(III)–Rh(III)-containing dimeric and oligomeric species [ 21 ].…”

Reactivity and Transformation of Antimetastatic and Cytotoxic Rhodium(III)–Dimethyl Sulfoxide Complexes in Biological Fluids: An XAS Speciation Study

“…Conversely, [ImH]- trans -[RhCl 4 ( 3 N-imidazole) 2 ], the Rh­(III)–imidazole analogue of KP1019, and [Na·2DMSO]- trans -[RhCl 4 ( S -dmso)­( 3 N -imidazole)], the Rh­(III) analogue of NAMI-A, were inactive both in vitro and in vivo. , Rh has stable oxidation states and coordination geometries of Rh­(III) (octahedral), Rh­(II) (dimeric lantern), Rh­(I) (square planar), respectively. , A number of bioactive complexes of each oxidation state have been evaluated in recent years (e.g., Rh­(I) N-heterocyclic carbenes, − photoactive Rh­(II)–polypyridyl complexes, , and organometallic Rh­(III)–Cp* agents (Cp* = pentamethylcyclopentadienyl ligand) − ). Notably, dirhodium­(II) tetraacetate, [Rh 2 (OAc) 4 ], readily reacted with methionine and cysteine under ambient conditions (aqueous solutions, pH 7.4, room temperature, and aerobic conditions) and generated various monomeric Rh­(III) species. − The Ru anticancer complexes have oxidation states of either Ru­(III) (e.g., NAMI-A and KP1019) or Ru­(II) (organometallic Ru­(II)–arene complexes , ). Reduction of Ru­(III) to Ru­(II) has been proposed to be the key mechanism of action for the anticancer activities of Ru­(III) complexes, but the latest biological speciation using X-ray absorption spectroscopy (XAS) argued strongly against this hypothesis. , Although detailed mechanistic studies on these Rh­(III) complexes were not pursued, these observations suggested alternative mechanisms of action for the anticancer activities of the Rh­(III) complexes in comparison to the much studied Ru and Pt anticancer drugs.…”

Kinetics of Reactions of Dirhodium and Diruthenium Paddlewheel Tetraacetate Complexes with Nucleophilic Protein Sites: Computational Insights

“…The dirhodium tetraacetate complex [Rh 2 (μ-O 2 CCH 3 ) 4 ] includes a Rh­(II)–Rh­(II) bond with four carboxylates playing the role of bridging ligands arranged in a lantern-like form around the central bimetal unit, whereas neutral solvent molecules (L) occupy the axial coordination sites. Although causing toxic side effects, this complex has a proven activity against several cancer types, such as sarcoma 180, P388 leukemia, L1210 tumors, and Ehrlich-Lettre ascites carcinoma. − Nevertheless, its mode of action is not yet disentangled despite several studies on its interaction with various proteins, − although it is hypothesized that its biomolecular targets are single- and double-stranded DNA, proteins, − peptides, , and amino acids. − Moreover, interaction of dirhodium compounds with peptides and proteins was investigated in the framework of protein modification with the aim of designing artificial metalloenzymes. , Usually, Rh-based complexes are coordinated to proteins either via the covalent linkage, involving direct binding of these metal complexes to proteins, , or via the dative anchoring which is based on the formation of noncovalent interactions between protein atoms and Rh ligands as well as coordinative bonds between protein side chains and Rh centers . There are experimental pieces of evidence of the Rh-complex selectivity toward side chains of Asn, Asp, His, Lys, and the C-terminal carboxylate. ,, …”