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

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

Auranofin, Et₃PAuCl, and Et₃PAuI Are Highly Cytotoxic on Colorectal Cancer Cells: A Chemical and Biological Study

The solution behavior of auranofin, Et₃PAuCl  and Et₃PAuI, as well as their interactions with hen egg white lysozyme, single strand oligonucleotide, and ds-DNA were comparatively analyzed through NMR spectroscopy, ESI-MS, ethidium bromide displacement, DNA melting and viscometric tests. The cytotoxic effects toward representative colorectal cancer cell lines were found to be strong and similar in the three cases and a good correlation could be established between the cytotoxicity and the ability to inhibit thioredoxin reductase; remarkably, <i>in vivo</i> acute toxicity experiments for Et₃PAuI confirmed that, similarly to auranofin, this drug is well tolerated in a murine model. Overall, a very similar profile emerges for Et₃PAuI and Et₃PAuCl, which retain the potent cytotoxic effects of auranofin while showing some peculiar features. These results demonstrate that the presence of the thiosugar moiety is not mandatory for the pharmacological action, suggesting that the tuning of some relevant chemical properties such as lipophilicity could be exploited to improve bioavailability, with no loss of the pharmacological effects

Reactivity and Biological Properties of a Series of Cytotoxic PtI₂(amine)₂ Complexes, Either <i>cis</i> or <i>trans</i> Configured

Six diiodido–diamine platinum­(II) complexes, either <i>cis</i> or <i>trans</i> configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the <i>trans</i> isomers being, generally, more effective than their <i>cis</i> counterparts. Cell cycle analysis revealed different modes of action for these new Pt­(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that <i>trans</i> complexes preferentially release their iodide ligands upon biomolecule binding, while the <i>cis</i> isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles

Reactivity and Biological Properties of a Series of Cytotoxic PtI₂(amine)₂ Complexes, Either <i>cis</i> or <i>trans</i> Configured

Six diiodido–diamine platinum­(II) complexes, either <i>cis</i> or <i>trans</i> configured, were prepared, differing only in the nature of the amine ligand (isopropylamine, dimethylamine, or methylamine), and their antiproliferative properties were evaluated against a panel of human tumor cell lines. Both series of complexes manifested pronounced cytotoxic effects, with the <i>trans</i> isomers being, generally, more effective than their <i>cis</i> counterparts. Cell cycle analysis revealed different modes of action for these new Pt­(II) complexes with respect to cisplatin. The reactivity of these platinum compounds with a number of biomolecules, including cytochrome c, two sulfur containing modified amino acids, 9-ethylguanine, and a single strand oligonucleotide, was analyzed in depth by mass spectrometry and NMR spectroscopy. Interestingly, significant differences in the reactivity of the investigated compounds toward the various model biomolecules were observed: in particular we observed that <i>trans</i> complexes preferentially release their iodide ligands upon biomolecule binding, while the <i>cis</i> isomers may release the amine ligands with retention of iodides. Such differences in reactivity may have important mechanistic implications and a relevant impact on the respective pharmacological profiles