Drastic effect of the peptide sequence on the copper-binding properties of tripeptides and the electrochemical behaviour of their copper(II) complexes

Silvia Mena, Andrea Mirats, Ana B. Caballero, Gonzalo Guirado, Leoní A. Barrios, Simon J. Teat, Luis Rodriguez-Santiago, Mariona Sodupe and Patrick Gamez

Chem. Eur. J. 2018, 24, 5153-5162

The binding and electrochemical properties of the complexes CuII‐HAH, CuII‐HWH, CuII‐Ac‐HWH, CuII‐HHW, and CuII‐WHH have been studied by using NMR and UV/Vis spectroscopies, CV, and density functional calculations. The results obtained highlight the importance of the peptidic sequence on the coordination properties and, consequently, on the redox properties of their CuII complexes. For CuII‐HAH and CuII‐HWH, no cathodic processes are observed up to −1.2 V; that is, the complexes exhibit very high stability towards copper reduction. This behaviour is associated with the formation of very stable square‐planar (5,5,6)‐membered chelate rings (ATCUN motif), which enclose two deprotonated amides. In contrast, for non‐ATCUN CuII‐Ac‐HWH, CuII‐HHW complexes, simulations seem to indicate that only one deprotonated amide is enclosed in the coordination sphere. In these cases, the main electrochemical feature is a reductive irreversible one electron‐transfer process from CuII to CuI, accompanied with structural changes of the metal coordination sphere and reprotonation of the amide. Finally, for CuII‐WHH, two major species have been detected: one at low pH (<5), with no deprotonated amides, and another one at high pH (>10) with an ATCUN motif, both species coexisting at intermediate pH. The present study shows that the use of CV, using glassy carbon as a working electrode, is an ideal and rapid tool for the determination of the redox properties of CuII metallopeptides.

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Photoactivation of the cytotoxic properties of platinum(II) complexes through ligand photoswitching

Andreu Presa, Guillem Vázquez, Leoní A. Barrios, Olivier Roubeau, Luís Korrodi-Gregório, Ricardo Pérez Tomás and Patrick Gamez

Inorg. Chem. 2018, 57, 4009-4022

The development of photoactivatable metal complexes with potential anticancer properties is a topical area of current investigation. Photoactivated chemotherapy using coordination compounds is typically based on photochemical processes occurring at the metal center. In the present study, an innovative approach is applied that takes advantage of the remarkable photochemical properties of diarylethenes. Following a proof-of-concept study with two complexes, namely, C1 and C2, a series of additional platinum(II) complexes from dithienylcyclopentene-based ligands was designed and prepared. Like C1 and C2, these new coordination compounds exhibit two thermally stable, interconvertible photoisomers that display distinct properties. The photochemical behavior of ligands L3–L7 has been analyzed by 1H NMR and UV–vis spectroscopies. Subsequently, the corresponding platinum(II) complexes C3–C7 were synthesized and fully characterized, including by single-crystal X-ray diffraction for some of them. Next, the interaction of each photoisomer (i.e., containing the open or closed ligand) of the metal complexes with DNA was examined thoroughly using various techniques, revealing their distinct DNA-binding modes and affinities, as observed for the earlier compounds C1 and C2. The antiproliferative activity of the two forms of the complexes was then assessed with five cancer cell lines and compared with that of C1 and C2, which supported the use of such diarylethene-based systems for the generation of a new class of potential photochemotherapeutic metallodrugs.

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Design, Synthesis, and Biological Evaluation of 1-Benzylamino-2-hydroxyalkyl Derivatives as New Potential Disease-Modifying Multifunctional Anti-Alzheimer's Agents

Dawid Panek, Anna Więckowska, Jakub Jończyk, Justyna Godyń, Marek Bajda, Tomasz Wichur, Anna Pasieka, Damijan Knez, Anja Pišlar, Jan Korabecny, Ondrej Soukup, Vendula Sepsova, Raimon Sabaté, Janko Kos, Stanislav Gobec and Barbara Malawska

ACS Chem. Neurosci. 2018, 9, 1074−1094

The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer’s disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, β-secretase, β-amyloid, and tau protein aggregation, all related to mechanisms which underpin Alzheimer’s disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets, inhibition of β-secretase (IC50 hBACE-1 = 41.60 μM), inhibition of amyloid β aggregation (IC50 Aβ = 3.09 μM), inhibition of tau aggregation (55% at 10 μM); as well as against symptomatic targets, butyrylcholinesterase inhibition (IC50 hBuChE = 7.22 μM). It might represent an encouraging starting point for development of multifunctional disease-modifying anti-Alzheimer’s agents.

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Evaluation of the metal-dependent cytotoxic behaviour of coordination compounds

Jordi Grau, Cristina Renau, Ana B. Caballero, Amparo Caubet, Marta Pockaj, Julia Lorenzo and  Patrick Gamez

Dalton Trans. 2018, 47, 4902-4908

The [Cu(L)Cl2]2 and [Pt(L)Cl2] complexes were prepared from the simple Schiff-base ligand (E)-phenyl-N-((pyridin-2-yl)methylene)methanamine (L) and respectively, CuCl2 and cis-[PtCl2(DMSO)2]. DNA-interaction studies revealed that the copper complex most likely acts as a DNA cleaver whereas the platinum complex binds to the double helix. Remarkably, cell-viability experiments with HeLa, MCF7 and PC3 cells showed that [Cu(L)Cl2]2 is an efficient cytotoxic agent whereas [Pt(L)Cl2] is not toxic, illustrating the crucial role played by the nature of the metal ion in the corresponding biological activity.

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DNA interaction of non-chelating tinidazole-based coordination compounds. Structural, redox and cytotoxic properties

Rodrigo Castro-Ramírez, Naytzé Ortiz-Pastrana, Ana Belén Caballero, Matthew T. Zimmerman, Bradley S. Stadelman, Andrea A. E. Gaertner, Julia L. Brumaghim, Luís Korrodi-Gregório, Ricardo Pérez Tomás, Patrick Gamez and Norah Barba Behrens

Dalton Trans. 2018, 47, 7551-7560

Novel tinidazole (tnz) coordination compounds of different geometries were synthesised, whose respective solid-state packing appears to be driven by inter- and intramolecular lone pair⋯π interactions. The copper(II) compounds exhibit interesting redox properties originating from both the tnz and the metal ions. These complexes interact with DNA through two distinct ways, namely via electrostatic interactions or/and groove binding, and they can mediate the generation of ROS that damage the biomolecule. Cytotoxic studies revealed an interesting activity of the dinuclear compound [Cu(tnz)2(μ-Cl)Cl]2 7, which is further more efficient towards cancer cells, compared with normal cells.

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Regioselective synthesis of 7-O-esters of the flavonolignan silibinin and SARs lead to compounds with overadditive neuroprotective effects

Simmon Schramm, Guozheng Huang, Sandra Gunesch, Florian Lang, Judit Roa, Petra Hogger, Raimon Sabaté, Pamela Maher, Michael Decker

A series of neuroprotective hybrid compounds was synthesized by conjugation of the flavonolignan silibinin with natural phenolic acids, such as ferulic, cinnamic and syringic acid. Selective 7-O-esterfication without protection groups was achieved by applying the respective acyl chlorides. Sixteen compounds were obtained and SARs were established by evaluating antioxidative properties in the physicochemical FRAP assay, as well as in a cell-based neuroprotection assay using murine hippocampal HT-22 cells. Despite weak activities in the FRAP assay, esters of the α,β-unsaturated acids showed pronounced overadditive effects at low concentrations greatly exceeding the effects of equimolar mixtures of silibinin and the respective acids in the neuroprotection assay. Cinnamic and ferulic acid esters (5a and 6a) also showed overadditive effects regarding inhibition of microglial activation, PC12 cell differentiation, in vitro ischemia as well as anti-aggregating abilities against Aβ42 peptide and τ protein. Remarkably, the esters of ferulic acid with silybin A and silybin B (11a and 11b) showed a moderate but significant difference in both neuroprotection and in their anti-aggregating capacities. The results demonstrate that non-toxic natural antioxidants can be regioselectively connected as esters with medium-term stability exhibiting very pronounced overadditive effects in a portfolio of biological assays.

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Efficient copper-based DNA cleavers from carboxylate benzimidazole ligands

Víctor A. Barrera-Guzmán, Edgar O. RodríguezHernández, Naytzé Ortíz-Pastrana, Ricardo Domínguez González, Ana B. Caballero, Patrick Gamez, Norah BarbaBehrens

J. Biol. Inorg. Chem. 2018, 23, 1165-1183

Four copper(II) coordination compounds from 2-benzimidazole propionic acid (Hbzpr) and 4-(benzimidazol-2-yl)-3-thiobutanoic acid (Hbztb) were synthesized and fully characterized by elemental analyses, electronic spectroscopy, FT-IR and mass spectrometry. The molecular structure for the four complexes was confirmed by single-crystal X-ray crystallography. The DNA-interacting properties of the two trinuclear and two mononuclear compounds were investigated using different spectroscopic techniques including absorption titration experiments, fluorescence spectroscopy and circular dichroism spectroscopy. Trinuclear [Cu3(bzpr)4(H2O)2](NO3)2·3H2O·CH3OH (2) and [Cu3(bzpr)4Cl2]·3H2O (3) bind to DNA through non-intercalative interactions, while for mononuclear [Cu(bzpr)2(H2O)]·2H2O (1) and [Cu(bztb)2]·2H2O (4), at minor concentrations in relation to the DNA, a groove binding interaction is favored, while at higher concentrations an intercalative mode is preferred. The nuclease properties of all complexes were studied by gel electrophoresis, which showed that they were able to cleave supercoiled plasmid DNA (form I) to the nicked form (form II). Compound 4 is even capable of generating linear form III (resulting from double-strand cleavage). The proposed mechanism of action involves an oxidative pathway (Fenton-type reaction), which produces harmful reactive species, like hydroxyl radicals.

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Highly Cytotoxic Ruthenium(II)-Arene Complexes from Bulky 1-Pyrenylphosphane Ligands

Rosa Brissos, Pau Clavero, Albert Gallen, Arnald Grabulosa, Leoní A. Barrios, Ana B. Caballero, Luís Korrodi-Gregório, Ricardo Perez-Tomas, Guillermo Muller, Vanessa Soto-Cerrato, Patrick Gamez

Inorg. Chem. 2018, 57, 14786-14797

In the present study, the potential anti-neoplastic properties of a series of ruthenium half-sandwich complexes of formula [Ru(η6-arene)Cl2(PR1R2(1-pyrenyl))] (η6-arene = p-cymene and R1 = R2 = methyl for 1; η6-arene = methylbenzoate and R1 = R2 = methyl for 2; η6-arene = p-cymene and R1 = R2 = phenyl for 3; η6-arene = methylbenzoate and R1 = R2 = phenyl for 4; η6-arene = p-cymene, R1 = methyl and R2 = phenyl for 5; η6-arene = methylbenzoate, R1 = methyl and R2 = phenyl for 6) have been investigated. The six structurally related organoruthenium(II) compounds have been prepared in good yields and fully characterized; the X-ray structures of three of them, i.e., 1, 2, and 4, were determined. Although the piano-stool compounds contain a large polycyclic aromatic moiety, viz. a 1-pyrenyl group, they do not appear to interact with DNA. However, all the piano-stool complexes show significant cytotoxic properties against five human cell lines, namely, lung adenocarcinoma (A549), melanoma (A375), colorectal adenocarcinoma (SW620), breast adenocarcinoma (MCF7), and nontumorigenic epithelial breast (MCF10A), with IC50 values in the micromolar range for most of them. In addition, the most active compound, i.e., 2, induces a remarkable decrease of cell viability, that is in the nanomolar range, against two human neuroblastoma cell lines, namely, SK-N-BE(2) and CHLA-90. Complexes 1–6 are all capable of inducing apoptosis, but with various degrees of magnitude. Whereas 1, 3, 5, and 6 have no effect on the cell cycle of A375 cells, 2 and 4 can arrest it at the G2/M phase; furthermore, 2 (which is the most efficient compound of the series) also stops the cycle at the S phase, behaving as the well-known anticancer agent cisplatin. Finally, 2 is able to inhibit/reduce the cell migration of neuroblastoma SK-N-BE(2) cells.

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Antiproliferative properties of iron supramolecular cylinders

Rosa F. Brissos, Luís Korrodi-Gregório, Ricardo Pérez-Tomás, Olivier Roubeau, Patrick Gamez

Chem. Sq. 2018, 2, 4

The use of metallohelicates as potential antiproliferative agents is mostly exemplified by one sole family of supramolecular compounds that is based on bis-iminopyridine ligands. In the present investigation, two other types of metallocylinders have been selected and their potential DNA-binding and cytotoxic properties have been investigated. Hence, two new neutral iron(III) metallosupramolecular compounds have been prepared from bis-β-diketone ligands, and a known cationic iron(II) helicate from bis-pyrazole ligands has been used for comparison purposes. DNA-interaction experiments and cell studies reveal remarkable biological properties for one of the neutral iron cylinders and the positively charged, pyrazole-based helicate, as illustrated by their antiproliferative behaviours, which are far better than those of two well-known compounds, i.e. the most studied metallohelicate in the field and cisplatin.

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