Protein Recognition of Gold-Based Drugs: 3D Structure of the Complex Formed When Lysozyme Reacts with Aubipy^c

The structure of the adduct formed in the reaction between Aubipy^c, a cytotoxic organogold­(III) compound, and the model protein hen egg white lysozyme (HEWL) has been solved by X-ray crystallography. It emerges that Aubipy^c, after interaction with HEWL, undergoes reduction of the gold­(III) center followed by detaching of the cyclometalated ligand; the resulting naked gold­(I) ion is found bound to the protein at Gln121. A direct comparison between the present structure and those previously solved for the lysozyme adducts with other gold­(III) compounds demonstrates that coordinated ligands play a key role in the protein–metallodrug recognition process. Structural data support the view that gold­(III)-based antitumor prodrugs are activated through metal reduction

Mesoionic Complexes of Platinum(II) Derived from “Rollover” Cyclometalation: A Delicate Balance between Pt–C(sp³) and Pt–C(sp²) Bond Cleavage as a Result of Different Reaction Conditions

“Rollover” cyclometalation is a particular case of metal-mediated C–H bond activation, and the resulting complexes constitute an emerging class of cyclometalated compounds. In the case of 2,2′-bipyridine “rollover cyclometalation” has been used to synthesize the complexes [Pt­(bipy-H)­(Me)­(L)] (L = PPh₃, PCy₃, P­(OPh)₃, P­(<i>p</i>-tolyl)₃), whose protonation produces a series of stable corresponding pyridylenes [Pt­(bipy*)­(Me)­(L)]⁺. The unusual bipy* ligand may be described as an abnormal-remote heterocyclic chelated carbene or simply as a mesoionic cyclometalated ligand. These cationic species spontaneously convert in solution, through a retro-rollover reaction, to the corresponding isomers [Pt­(bipy)­(Me)­(L)]⁺, where the 2,2′-bipyridine is coordinated in the classical N,N bidentate mode. Isomerization is achieved at different rates (ranging over three orders of magnitude), depending on the nature of the phosphane ligand, the most basic (PCy₃) providing the fastest reaction. The mesoionic species [Pt­(bipy*)­(Me)­(L)]⁺ contain two Pt–C bonds: the balance between the Pt–C­(sp²) and Pt–C­(sp³) bond rupture is subtle, and competition is observed according to the reaction conditions. In the presence of an external neutral ligand L′ methane is released to give the cationic derivatives [Pt­(bipy-H)­(L)­(L′)]⁺, whereas reaction of the neutral [Pt­(bipy-H)­(Me)­(L)] with HCl may follow different routes depending on the nature of the neutral ligand L. Assuming all reactions take place through the formation of a hydride intermediate, quantum chemical calculations show that computed energy barriers are qualitatively consistent with observed reaction rates

Rollover Cyclometalation with 2‑(2′-Pyridyl)quinoline

Rollover cyclometalation of 2-(2′-pyridyl)­quinoline, L, allowed the synthesis of the family of complexes [Pt­(L-H)­(X)­(L′)] and [Pt­(L*)­(X)­(L′)]­[BF₄] (X = Me, Cl; L′ = neutral ligand), the former being the first examples of Pt­(II) rollover complexes derived from the ligand L. The ligand L* is a C,N cyclometalated, N-protonated isomer of L, and can also be described as an abnormal-remote pyridylene. The corresponding [Pt­(L-H)­(Me)­(L′)]/[Pt­(L*)­(Me)­(L′)]⁺ complexes constitute an uncommon Brønsted–Lowry acid–base conjugated couple. The species obtained were investigated in depth through NMR and UV–vis spectroscopy, cyclic voltammetry, and density functional theory (DFT) methods to correlate different chemico-physical properties with the nature of the cyclometalated ligand (e.g., L vs bipy or L* vs L) and of the neutral ligand (DMSO, CO, PPh₃). The crystal structures of [Pt­(L-H)­(Me)­(PPh₃)], [Pt­(L-H)­(Me)­(CO)] and [Pt­(L*)­(Me)­(CO)]­[BF₄] were determined by X-ray powder diffraction methods, the latter being the first structure of a Pt­(II)-based, protonated, rollover complex to be unraveled. The isomerization of [Pt­(L*)­(Me)­(PPh₃)]⁺ in solution proceeds through a retro-rollover process to give the corresponding adduct [Pt­(L)­(Me)­(PPh₃)]⁺, where L acts as a classical N,N chelating ligand. Notably, the retro-rollover reaction is the first process, among the plethora of Pt–C bond protonolysis reactions reported in the literature, where a Pt–C­(heteroaryl) bond is cleaved rather than a Pt–C­(alkyl) one

Rollover Cyclometalation with 2‑(2′-Pyridyl)quinoline

Rollover cyclometalation of 2-(2′-pyridyl)­quinoline, L, allowed the synthesis of the family of complexes [Pt­(L-H)­(X)­(L′)] and [Pt­(L*)­(X)­(L′)]­[BF₄] (X = Me, Cl; L′ = neutral ligand), the former being the first examples of Pt­(II) rollover complexes derived from the ligand L. The ligand L* is a C,N cyclometalated, N-protonated isomer of L, and can also be described as an abnormal-remote pyridylene. The corresponding [Pt­(L-H)­(Me)­(L′)]/[Pt­(L*)­(Me)­(L′)]⁺ complexes constitute an uncommon Brønsted–Lowry acid–base conjugated couple. The species obtained were investigated in depth through NMR and UV–vis spectroscopy, cyclic voltammetry, and density functional theory (DFT) methods to correlate different chemico-physical properties with the nature of the cyclometalated ligand (e.g., L vs bipy or L* vs L) and of the neutral ligand (DMSO, CO, PPh₃). The crystal structures of [Pt­(L-H)­(Me)­(PPh₃)], [Pt­(L-H)­(Me)­(CO)] and [Pt­(L*)­(Me)­(CO)]­[BF₄] were determined by X-ray powder diffraction methods, the latter being the first structure of a Pt­(II)-based, protonated, rollover complex to be unraveled. The isomerization of [Pt­(L*)­(Me)­(PPh₃)]⁺ in solution proceeds through a retro-rollover process to give the corresponding adduct [Pt­(L)­(Me)­(PPh₃)]⁺, where L acts as a classical N,N chelating ligand. Notably, the retro-rollover reaction is the first process, among the plethora of Pt–C bond protonolysis reactions reported in the literature, where a Pt–C­(heteroaryl) bond is cleaved rather than a Pt–C­(alkyl) one

Rollover Cyclometalation with 2‑(2′-Pyridyl)quinoline

Rollover cyclometalation of 2-(2′-pyridyl)­quinoline, L, allowed the synthesis of the family of complexes [Pt­(L-H)­(X)­(L′)] and [Pt­(L*)­(X)­(L′)]­[BF₄] (X = Me, Cl; L′ = neutral ligand), the former being the first examples of Pt­(II) rollover complexes derived from the ligand L. The ligand L* is a C,N cyclometalated, N-protonated isomer of L, and can also be described as an abnormal-remote pyridylene. The corresponding [Pt­(L-H)­(Me)­(L′)]/[Pt­(L*)­(Me)­(L′)]⁺ complexes constitute an uncommon Brønsted–Lowry acid–base conjugated couple. The species obtained were investigated in depth through NMR and UV–vis spectroscopy, cyclic voltammetry, and density functional theory (DFT) methods to correlate different chemico-physical properties with the nature of the cyclometalated ligand (e.g., L vs bipy or L* vs L) and of the neutral ligand (DMSO, CO, PPh₃). The crystal structures of [Pt­(L-H)­(Me)­(PPh₃)], [Pt­(L-H)­(Me)­(CO)] and [Pt­(L*)­(Me)­(CO)]­[BF₄] were determined by X-ray powder diffraction methods, the latter being the first structure of a Pt­(II)-based, protonated, rollover complex to be unraveled. The isomerization of [Pt­(L*)­(Me)­(PPh₃)]⁺ in solution proceeds through a retro-rollover process to give the corresponding adduct [Pt­(L)­(Me)­(PPh₃)]⁺, where L acts as a classical N,N chelating ligand. Notably, the retro-rollover reaction is the first process, among the plethora of Pt–C bond protonolysis reactions reported in the literature, where a Pt–C­(heteroaryl) bond is cleaved rather than a Pt–C­(alkyl) one

Rollover Cyclometalation with 2‑(2′-Pyridyl)quinoline

Rollover cyclometalation of 2-(2′-pyridyl)­quinoline, L, allowed the synthesis of the family of complexes [Pt­(L-H)­(X)­(L′)] and [Pt­(L*)­(X)­(L′)]­[BF₄] (X = Me, Cl; L′ = neutral ligand), the former being the first examples of Pt­(II) rollover complexes derived from the ligand L. The ligand L* is a C,N cyclometalated, N-protonated isomer of L, and can also be described as an abnormal-remote pyridylene. The corresponding [Pt­(L-H)­(Me)­(L′)]/[Pt­(L*)­(Me)­(L′)]⁺ complexes constitute an uncommon Brønsted–Lowry acid–base conjugated couple. The species obtained were investigated in depth through NMR and UV–vis spectroscopy, cyclic voltammetry, and density functional theory (DFT) methods to correlate different chemico-physical properties with the nature of the cyclometalated ligand (e.g., L vs bipy or L* vs L) and of the neutral ligand (DMSO, CO, PPh₃). The crystal structures of [Pt­(L-H)­(Me)­(PPh₃)], [Pt­(L-H)­(Me)­(CO)] and [Pt­(L*)­(Me)­(CO)]­[BF₄] were determined by X-ray powder diffraction methods, the latter being the first structure of a Pt­(II)-based, protonated, rollover complex to be unraveled. The isomerization of [Pt­(L*)­(Me)­(PPh₃)]⁺ in solution proceeds through a retro-rollover process to give the corresponding adduct [Pt­(L)­(Me)­(PPh₃)]⁺, where L acts as a classical N,N chelating ligand. Notably, the retro-rollover reaction is the first process, among the plethora of Pt–C bond protonolysis reactions reported in the literature, where a Pt–C­(heteroaryl) bond is cleaved rather than a Pt–C­(alkyl) one

Structure–Activity Relationships in Cytotoxic Au^I/Au^III Complexes Derived from 2‑(2′-Pyridyl)benzimidazole

Gold­(I) and gold­(III) complexes derived from 2-(2′-pyridyl)­benzimidazole (pbiH) were proven to be a promising class of in vitro antitumor agents against A2780 human ovarian cancer cells. In this paper, a comparative electrochemical, UV–vis absorption, and emission spectroscopic investigation is reported on pbiH, the two mononuclear Au^III complexes [(pbi)­AuX₂] (X = Cl (<b>1</b>), AcO (<b>2</b>)), the four mononuclear Au^I derivatives [(pbiH)­AuCl] (<b>3</b>), [(pbiH)­Au­(PPh₃)]­PF₆ ((<b>4</b>⁺)­(PF₆^–)), [(pbi)­Au­(PPh₃)] (<b>5</b>), and [(pbi)­Au­(TPA)] (<b>6</b>), the three mixed-valence Au^III/Au^I complexes [(μ-pbi)­Au₂Cl₃] (<b>7</b>), [(Ph₃P)­Au­(μ-pbi)­AuX₂]­PF₆ (X = Cl ((<b>8</b>⁺)­(PF₆^–)), AcO ((<b>9</b>⁺)­(PF₆^–))), and the binuclear Au^I–Au^I compound [(μ-pbi)­Au₂(PPh₃)₂]­PF₆ ((<b>10</b>⁺)­(PF₆^–)). All complexes feature irreversible reduction processes related to the Au^III/Au^I or Au^I/Au⁰ processes and peculiar luminescent emission at about 360–370 nm in CH₂Cl₂, with quantum yields that are remarkably lower ((0.7–14.5) × 10^–2) in comparison to that determined for the free pbiH ligand (31.5 × 10^–2) in the same solvent. The spectroscopic and electrochemical properties of all complexes were interpreted on the grounds of time-dependent PBE0/DFT calculations carried out both in the gas phase and in CH₂Cl₂ implicitly considered within the IEF-PCM SCRF approach. The electronic structure of the complexes, and in particular the energy and composition of the Kohn–Sham LUMOs, can be related to the antiproliferative properties against the A2780 ovarian carcinoma cell line, providing sound quantitative structure–activity relationships and shedding a light on the role played by the global charge and nature of ancillary ligands in the effectiveness of Au-based antitumor drugs

Heterobimetallic Rollover Derivatives

Heterobimetallic complexes with metal centers connected by a small delocalized ligand constitute an interesting class of compounds. Here we report that starting from the mononuclear platinum­(II) rollover complexes [Pt­(bipy-H)­(L)­Cl] (bipy-H = 2,2′-bipyridine C(3′)-N cyclometalated, L= DMSO, PPh₃) a second rollover cyclometalation may produce a series of Pt­(II)/Pd­(II) heterobimetallic complexes where the two metals are linked by the planar, highly delocalized, doubly deprotonated 2,2′-bipyridine

Heterobimetallic Rollover Derivatives

Heterobimetallic complexes with metal centers connected by a small delocalized ligand constitute an interesting class of compounds. Here we report that starting from the mononuclear platinum­(II) rollover complexes [Pt­(bipy-H)­(L)­Cl] (bipy-H = 2,2′-bipyridine C(3′)-N cyclometalated, L= DMSO, PPh₃) a second rollover cyclometalation may produce a series of Pt­(II)/Pd­(II) heterobimetallic complexes where the two metals are linked by the planar, highly delocalized, doubly deprotonated 2,2′-bipyridine