Cisplatin Binding to Proteins: Molecular Structure of the Ribonuclease A Adduct

The crystal structure of the main adduct formed in the reaction between cisplatin and bovine pancreatic ribonuclease is reported here. Notably, in both of the protein molecules present in the asymmetric unit, platinum­(II) binding takes place exclusively at the level of Met29. In one of the two molecules, the Gln28 side chain completes the platinum coordination sphere, anchoring the cisplatin fragment to the protein in a bidentate fashion. These results contain interesting implications for understanding the biological chemistry of this important drug

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

Promising <i>in Vitro</i> anti-Alzheimer Properties for a Ruthenium(III) Complex

Metal complexes represent today an attractive class of experimental anti-Alzheimer agents with the potential of blocking β-amyloid 1–42 aggregation and scavenging its toxicity. Three representative ruthenium­(III) complexes, namely NAMI A, KP1019, and PMRU20, were specifically evaluated to this end in an established <i>in vitro</i> model of AD relying on primary cortical neurons. Notably, PMRU20 turned out to be highly effective in protecting cortical neurons against Aβ 1–42 toxicity, while the other tested ruthenium compounds were poorly active or even inactive; we also found that PMRU20 is virtually devoid of any significant toxicity <i>in vitro</i> at the applied concentrations. Interestingly, PMRU20 was neuroprotective even against the toxicity induced by Aβ 25–35. The direct reaction of PMRU20 with Aβ 1–42 was explored through ESI MS analysis and some adduct formation evidenced. In addition, thioflavin T assays revealed that PMRU20 greatly reduces Aβ 1–42 aggregation. The implications of these findings are discussed in relation to emerging treatment strategies for the Alzheimer’s disease

Peculiar Features in the Crystal Structure of the Adduct Formed between <i>cis</i>-PtI₂(NH₃)₂ and Hen Egg White Lysozyme

The reactivity of <i>cis</i>-diamminediiodidoplatinum­(II), <i>cis</i>-PtI₂(NH₃)₂, the iodo analogue of cisplatin, with hen egg white lysozyme (HEWL) was investigated by electrospray ionization mass spectrometry and X-ray crystallography. Interestingly, the study compound forms a stable 1:1 protein adduct for which the crystal structure was solved at 1.99 Å resolution. In this adduct, the Pt^II center, upon release of one ammonia ligand, selectively coordinates to the imidazole of His15. Both iodide ligands remain bound to platinum, with this being a highly peculiar and unexpected feature. Notably, two equivalent modes of Pt^II binding are possible that differ only in the location of I atoms with respect to ND1 of His15. The structure of the adduct was compared with that of HEWL–cisplatin, previously described; differences are stressed and their important mechanistic implications discussed

Interactions between Anticancer <i>trans</i>-Platinum Compounds and Proteins: Crystal Structures and ESI-MS Spectra of Two Protein Adducts of <i>trans</i>-(Dimethylamino)(methylamino)dichloridoplatinum(II)

The adducts formed between <i>trans</i>-(dimethylamino)­(methylamino)­dichloridoplatinum­(II), [t-PtCl₂(dma)­(ma)], and two model proteins, i.e., hen egg white lysozyme and bovine pancreatic ribonuclease, were independently characterized by X-ray crystallography and electrospray ionization mass spectrometry. In these adducts, the Pt^II center, upon chloride release, coordinates either to histidine or aspartic acid residues while both alkylamino ligands remain bound to the metal. Comparison with the cisplatin derivatives of the same proteins highlights for [t-PtCl₂(dma)­(ma)] a kind of biomolecular metalation remarkably different from that of cisplatin

Large Protein Assemblies for High-Relaxivity Contrast Agents: The Case of Gadolinium-Labeled Asparaginase

Biologics are emerging as the most important class of drugs and are used to treat a large variety of pathologies. Most of biologics are proteins administered in large amounts, either by intramuscular injection or by intravenous infusion. Asparaginase is a large tetrameric protein assembly, currently used against acute lymphoblastic leukemia. Here, a gadolinium(III)-DOTA derivative has been conjugated to asparaginase, and its relaxation properties have been investigated to assess its efficiency as a possible theranostic agent. The field-dependent 1H longitudinal relaxation measurements of water solutions of gadolinium(III)-labeled asparaginase indicate a very large increase in the relaxivity of this paramagnetic protein complex with respect to small gadolinium chelates, opening up the possibility of its use as an MRI contrast agent

Synthesis, Structural Characterization, Solution Behavior, and in Vitro Antiproliferative Properties of a Series of Gold Complexes with 2-(2′-Pyridyl)benzimidazole as Ligand: Comparisons of Gold(III) versus Gold(I) and Mononuclear versus Binuclear Derivatives

A variety of gold­(III) and gold­(I) derivatives of 2-(2′-pyridyl)­benzimidazole (pbiH) were synthesized and fully characterized and their antiproliferative properties evaluated in a representative ovarian cancer cell line. The complexes include the mononuclear species [(pbi)­AuX₂] (X = Cl, <b>1</b>; OAc, <b>2</b>), [(pbiH)­AuCl] (<b>3</b>), [(pbiH)­Au­(PPh₃)]­[PF₆] (<b>4</b>-PF₆), and [(pbi)­Au­(L)] (L = PPh₃, <b>5</b>; TPA, <b>6</b>), and the binuclear gold­(I)/gold­(I) and gold­(I)/gold­(III) derivatives [(PPh₃)₂Au₂(μ₂-pbi)]­[PF₆] (<b>10</b>-PF₆), [ClAu­(μ₃-pbi)­AuCl₂] (<b>7</b>), and [(PPh₃)­Au­(μ₃-pbi)­AuX₂]­[PF₆] (X = Cl, <b>8</b>-PF₆; OAc, <b>9</b>-PF₆). The molecular structures of <b>6</b>, <b>7</b>, and <b>10</b>-PF₆ were determined by X-ray diffraction analysis. The chemical behavior of these compounds in solution was analyzed both by cyclic voltammetry in DMF and absorption UV–vis spectroscopy in an aqueous buffer. Overall, the stability of these gold compounds was found to be acceptable for the cellular studies. For all complexes, relevant antiproliferative activities in vitro were documented against A2780 human ovarian carcinoma cells, either resistant or sensitive to cisplatin, with IC₅₀ values falling in the low micromolar or even in the nanomolar range. The investigated gold compounds were found to overcome resistance to cisplatin to a large degree. Results are interpreted and discussed in the frame of current knowledge on cytotoxic and antitumor gold compounds

Synthesis, Structural Characterization, Solution Behavior, and in Vitro Antiproliferative Properties of a Series of Gold Complexes with 2-(2′-Pyridyl)benzimidazole as Ligand: Comparisons of Gold(III) versus Gold(I) and Mononuclear versus Binuclear Derivatives

A variety of gold­(III) and gold­(I) derivatives of 2-(2′-pyridyl)­benzimidazole (pbiH) were synthesized and fully characterized and their antiproliferative properties evaluated in a representative ovarian cancer cell line. The complexes include the mononuclear species [(pbi)­AuX₂] (X = Cl, <b>1</b>; OAc, <b>2</b>), [(pbiH)­AuCl] (<b>3</b>), [(pbiH)­Au­(PPh₃)]­[PF₆] (<b>4</b>-PF₆), and [(pbi)­Au­(L)] (L = PPh₃, <b>5</b>; TPA, <b>6</b>), and the binuclear gold­(I)/gold­(I) and gold­(I)/gold­(III) derivatives [(PPh₃)₂Au₂(μ₂-pbi)]­[PF₆] (<b>10</b>-PF₆), [ClAu­(μ₃-pbi)­AuCl₂] (<b>7</b>), and [(PPh₃)­Au­(μ₃-pbi)­AuX₂]­[PF₆] (X = Cl, <b>8</b>-PF₆; OAc, <b>9</b>-PF₆). The molecular structures of <b>6</b>, <b>7</b>, and <b>10</b>-PF₆ were determined by X-ray diffraction analysis. The chemical behavior of these compounds in solution was analyzed both by cyclic voltammetry in DMF and absorption UV–vis spectroscopy in an aqueous buffer. Overall, the stability of these gold compounds was found to be acceptable for the cellular studies. For all complexes, relevant antiproliferative activities in vitro were documented against A2780 human ovarian carcinoma cells, either resistant or sensitive to cisplatin, with IC₅₀ values falling in the low micromolar or even in the nanomolar range. The investigated gold compounds were found to overcome resistance to cisplatin to a large degree. Results are interpreted and discussed in the frame of current knowledge on cytotoxic and antitumor gold compounds

Chemistry and Biology of Two Novel Gold(I) Carbene Complexes as Prospective Anticancer Agents

Two novel gold carbene compounds, namely, chlorido (1-butyl-3-methyl-imidazole-2-ylidene) gold­(I) (<b>1</b>) and bis­(1-butyl-3-methyl-imidazole-2-ylidene) gold­(I) (<b>2</b>), were prepared and characterized as prospective anticancer drug candidates. These compounds consist of a gold­(I) center linearly coordinated either to one N-heterocyclic carbene (NHC) and one chloride ligand (<b>1</b>) or to two identical NHC ligands (<b>2</b>). Crystal structures were solved for both compounds, the resulting structural data being in good agreement with expectations. We wondered whether the presence of two tight carbene ligands in <b>2</b> might lead to biological properties distinct from those of the monocarbene complex <b>1</b>. Notably, in spite of their appreciable structural differences, these two compounds manifested similarly potent cytotoxic actions in vitro when challenged against A2780 human ovarian carcinoma cells. In addition, both were able to overcome resistance to cisplatin in the A2780R line. Solution studies revealed that these gold carbene complexes are highly stable in aqueous buffers at physiological pH. Their reactivity with proteins was explored: no adduct formation was detected even upon a long incubation with the model proteins cytochrome c and lysozyme; in contrast, both compounds were able to metalate, to a large extent, the copper chaperone Atox-1, bearing a characteristic CXXC motif. The precise nature of the resulting gold-Atox-1 adducts was elucidated through ESI-MS analysis. On the basis of these findings, it is proposed that the investigated gold­(I) carbene compounds are promising antiproliferative agents warranting a wider pharmacological evaluation. Most likely these gold compounds produce their potent biological effects through selective metalation and impairment of a few crucial cellular proteins

Chemistry and Biology of Two Novel Gold(I) Carbene Complexes as Prospective Anticancer Agents

Two novel gold carbene compounds, namely, chlorido (1-butyl-3-methyl-imidazole-2-ylidene) gold­(I) (<b>1</b>) and bis­(1-butyl-3-methyl-imidazole-2-ylidene) gold­(I) (<b>2</b>), were prepared and characterized as prospective anticancer drug candidates. These compounds consist of a gold­(I) center linearly coordinated either to one N-heterocyclic carbene (NHC) and one chloride ligand (<b>1</b>) or to two identical NHC ligands (<b>2</b>). Crystal structures were solved for both compounds, the resulting structural data being in good agreement with expectations. We wondered whether the presence of two tight carbene ligands in <b>2</b> might lead to biological properties distinct from those of the monocarbene complex <b>1</b>. Notably, in spite of their appreciable structural differences, these two compounds manifested similarly potent cytotoxic actions in vitro when challenged against A2780 human ovarian carcinoma cells. In addition, both were able to overcome resistance to cisplatin in the A2780R line. Solution studies revealed that these gold carbene complexes are highly stable in aqueous buffers at physiological pH. Their reactivity with proteins was explored: no adduct formation was detected even upon a long incubation with the model proteins cytochrome c and lysozyme; in contrast, both compounds were able to metalate, to a large extent, the copper chaperone Atox-1, bearing a characteristic CXXC motif. The precise nature of the resulting gold-Atox-1 adducts was elucidated through ESI-MS analysis. On the basis of these findings, it is proposed that the investigated gold­(I) carbene compounds are promising antiproliferative agents warranting a wider pharmacological evaluation. Most likely these gold compounds produce their potent biological effects through selective metalation and impairment of a few crucial cellular proteins