Inorganics

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5 pages, 188 KiB

Open AccessEditorial

Bioinorganic Chemistry of Copper: From Biochemistry to Pharmacology

by Ana Maria Da Costa Ferreira, Christelle Hureau and Gianella Facchin

Inorganics 2024, 12(4), 97; https://doi.org/10.3390/inorganics12040097 - 28 Mar 2024

Cited by 1 | Viewed by 1672

Abstract

Copper is an essential trace element found ubiquitously in humans [...] Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

Research

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14 pages, 3456 KiB

Open AccessArticle

Pentadentate and Hexadentate Pyridinophane Ligands Support Reversible Cu(II)/Cu(I) Redox Couples

by Glenn Blade, Andrew J. Wessel, Karna Terpstra and Liviu M. Mirica

Inorganics 2023, 11(11), 446; https://doi.org/10.3390/inorganics11110446 - 20 Nov 2023

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Abstract

Two new ligands were synthesized with the goal of copper stabilization, N,N′-(2-methylpyridine)-2,11-diaza[3,3](2,6)pyridinophane (^PicN4) and N-(methyl),N′-(2-methylpyridine)-2,11-diaza[3,3](2,6)pyridinophane (^PicMeN4), by selective functionalization of ^HN4 and ^TsHN4. These two ligands, when reacted with various copper salts, generated both Cu(II) and Cu(I) [...] Read more.

Two new ligands were synthesized with the goal of copper stabilization, N,N′-(2-methylpyridine)-2,11-diaza[3,3](2,6)pyridinophane (^PicN4) and N-(methyl),N′-(2-methylpyridine)-2,11-diaza[3,3](2,6)pyridinophane (^PicMeN4), by selective functionalization of ^HN4 and ^TsHN4. These two ligands, when reacted with various copper salts, generated both Cu(II) and Cu(I) complexes. These ligands and Cu complexes were characterized by various methods, such as NMR, UV-Vis, MS, and EA. Each compound was also examined electrochemically, and each revealed reversible Cu(II)/Cu(I) redox couples. Additionally, stability constants were determined via spectrophotometric titrations, and radiolabeling and cytotoxicity experiments were performed to assess the chelators relevance to their potential use in vivo as ⁶⁴Cu PET imaging agents. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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13 pages, 3407 KiB

Open AccessArticle

Exploration of Lycorine and Copper(II)’s Association with the N-Terminal Domain of Amyloid β

by Arian Kola, Ginevra Vigni and Daniela Valensin

Inorganics 2023, 11(11), 443; https://doi.org/10.3390/inorganics11110443 - 18 Nov 2023

Cited by 1 | Viewed by 1943

Abstract

Lycorine (LYC) is an active alkaloid first isolated from Narcissus pseudonarcissus and found in most Amaryllidaceae plants. It belongs to the same family as galantamine, which is the active component of a drug used for the treatment of Alzheimer’s disease. Similarly to galantamine, [...] Read more.

Lycorine (LYC) is an active alkaloid first isolated from Narcissus pseudonarcissus and found in most Amaryllidaceae plants. It belongs to the same family as galantamine, which is the active component of a drug used for the treatment of Alzheimer’s disease. Similarly to galantamine, LYC is able to suppress induced amyloid β (Aβ) toxicity in differentiated SH-SY5Y cell lines and it can weakly interact with the N-terminal region of Aβ via electrostatic interactions. The N-terminal Aβ domain is also involved in Cu(II)/Cu(I) binding and the formed complexes are known to play a key role in ROS production. In this study, the Aβ–LYC interaction in the absence and in the presence of copper ions was investigated by using the N-terminal Aβ peptide encompassing the first 16 residues. NMR analysis showed that Aβ can simultaneously interact with Cu(II) and LYC. The Cu(II) binding mode remains unchanged in the presence of LYC, while LYC association is favored when an Aβ–Cu(II) complex is formed. Moreover, UV-VIS studies revealed the ability of LYC to interfere with the catalytic activities of the Aβ–Cu(II) complexes by reducing the ascorbate consumption monitored at 265 nm. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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19 pages, 3453 KiB

Open AccessArticle

Effect of Metal Environment and Immobilization on the Catalytic Activity of a Cu Superoxide Dismutase Mimic

by Micaela Richezzi, Joaquín Ferreyra, Sharon Signorella, Claudia Palopoli, Gustavo Terrestre, Nora Pellegri, Christelle Hureau and Sandra R. Signorella

Inorganics 2023, 11(11), 425; https://doi.org/10.3390/inorganics11110425 - 27 Oct 2023

Cited by 1 | Viewed by 1749

Abstract

The Cu(II)/Cu(I) conversion involves variation in the coordination number and geometry around the metal center. Therefore, the flexibility/rigidity of the ligand plays a critical role in the design of copper superoxide dismutase (SOD) mimics. A 1,3-Bis[(pyridin-2-ylmethyl)(propargyl)amino]propane (pypapn), a flexible ligand with an N [...] Read more.

The Cu(II)/Cu(I) conversion involves variation in the coordination number and geometry around the metal center. Therefore, the flexibility/rigidity of the ligand plays a critical role in the design of copper superoxide dismutase (SOD) mimics. A 1,3-Bis[(pyridin-2-ylmethyl)(propargyl)amino]propane (pypapn), a flexible ligand with an N₄-donor set, was used to prepare [Cu(pypapn)(ClO₄)₂], a trans-Cu(II) complex whose structure was determined by the X-ray diffraction. In DMF or water, perchlorate anions are exchanged with solvent molecules, affording [Cu(pypan)(solv)₂]²⁺ that catalyzes O₂^•− dismutation with a second-order rate constant k_McF = 1.26 × 10⁷ M⁻¹ s⁻¹, at pH 7.8. This high activity results from a combination of ligand flexibility, total charge, and labile binding sites, which places [Cu(pypapn)(solv)₂]²⁺ above other mononuclear Cu(II) complexes with more favorable redox potentials. The covalent anchoring of the alkyne group of the complex to azide functionalized mesoporous silica through “click” chemistry resulted in the retention of the SOD activity and improved stability. A dicationic Cu(II)-N₄-Schiff base complex encapsulated in mesoporous silica was also tested as an SOD mimic, displaying higher activity than the free complex, although lower than [Cu(pypapn)(solv)₂]²⁺. The robustness of covalently attached or encapsulated doubly charged Cu(II) complexes in a mesoporous matrix appears as a suitable approach for the design of copper-based hybrid catalysts for O₂^•− dismutation under physiological conditions. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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16 pages, 3191 KiB

Open AccessArticle

Antiparasitic Activity of Oxindolimine–Metal Complexes against Chagas Disease

by Marcelo Cecconi Portes, Grazielle Alves Ribeiro, Gustavo Levendoski Sabino, Ricardo Alexandre Alves De Couto, Leda Quércia Vieira, Maria Júlia Manso Alves and Ana Maria Da Costa Ferreira

Inorganics 2023, 11(11), 420; https://doi.org/10.3390/inorganics11110420 - 24 Oct 2023

Cited by 1 | Viewed by 1761

Abstract

Some copper(II) and zinc(II) complexes with oxindolimine ligands were tested regarding their trypanocidal properties. These complexes have already shown good biological activity in the inhibition of tumor cell proliferation, having DNA and mitochondria as main targets, through an oxidative mechanism, and inducing apoptosis. [...] Read more.

Some copper(II) and zinc(II) complexes with oxindolimine ligands were tested regarding their trypanocidal properties. These complexes have already shown good biological activity in the inhibition of tumor cell proliferation, having DNA and mitochondria as main targets, through an oxidative mechanism, and inducing apoptosis. Herein, we demonstrate that they also have significant activity against the infective trypomastigote forms and the intracellular amastigote forms of T. cruzi, modulated by the metal ion as well as by the oxindolimine ligand. Selective indexes (LC₅₀/IC₅₀) determined for both zinc(II) and copper(II) complexes, are higher after 24 or 48 h incubation with trypomastigotes, in comparison to traditional drugs used in clinics, such as benznidazole, and other metal-based compounds previously reported in the literature. Additionally, tests against amastigotes indicated infection index <10% (% of infected macrophages/average number of amastigotes per macrophage), after 24 or 48 h in the presence of zinc(II) (60–80 µM) or analogous copper(II) complexes (10–25 µM). The copper complexes exhibit further oxidative properties, being able to damage DNA, proteins and carbohydrates, in the presence of hydrogen peroxide, with the generation of hydroxyl radicals. This redox reactivity could explain its better performance towards the parasites in relation to the zinc analogs. However, both copper and zinc complexes display good selective indexes, indicating that the influence of the ligand is also crucial, and is probably related to the inhibition of some crucial proteins. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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12 pages, 2023 KiB

Open AccessArticle

Synthesis, Characterization, DNA Binding and Cytotoxicity of Copper(II) Phenylcarboxylate Complexes

by Carlos Y. Fernández, Analu Rocha, Mohammad Azam, Natalia Alvarez, Kim Min, Alzir A. Batista, Antonio J. Costa-Filho, Javier Ellena and Gianella Facchin

Inorganics 2023, 11(10), 398; https://doi.org/10.3390/inorganics11100398 - 11 Oct 2023

Cited by 1 | Viewed by 1741

Abstract

Coordination compounds of copper exhibit cytotoxic activity and are suitable for the search for novel drug candidates for cancer treatment. In this work, we synthesized three copper(II) carboxylate complexes, [Cu₂(3-(4-hydroxyphenyl)propanoate)₄(H₂O)₂]·2H₂O (C1), [...] Read more.

Coordination compounds of copper exhibit cytotoxic activity and are suitable for the search for novel drug candidates for cancer treatment. In this work, we synthesized three copper(II) carboxylate complexes, [Cu₂(3-(4-hydroxyphenyl)propanoate)₄(H₂O)₂]·2H₂O (C1), [Cu₂(phenylpropanoate)₄(H₂O)₂] (C2) and [Cu₂(phenylacetate)₄] (C3), and characterized them by elemental analysis and spectroscopic methods. Single-crystal X-ray diffraction of C1 showed the dinuclear paddle-wheel arrangement typical of Cu–carboxylate complexes in the crystal structure. In an aqueous solution, the complexes remain as dimeric units, as studied by UV-visible spectroscopy. The lipophilicity (partition coefficient) and the DNA binding (UV visible and viscosity) studies evidence that the complexes bind the DNA with low K_b constants. In vitro cytotoxicity studies on human cancer cell lines of metastatic breast adenocarcinoma (MDA-MB-231, MCF-7), lung epithelial carcinoma (A549) and cisplatin-resistant ovarian carcinoma (A2780cis), as well as a nontumoral lung cell line (MRC-5), indicate that the complexes are cytotoxic in cisplatin-resistant cells. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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22 pages, 3632 KiB

Open AccessArticle

Anti-Proliferation and DNA Cleavage Activities of Copper(II) Complexes of N₃O Tripodal Polyamine Ligands

by Doti Serre, Sule Erbek, Nathalie Berthet, Christian Philouze, Xavier Ronot, Véronique Martel-Frachet and Fabrice Thomas

Inorganics 2023, 11(10), 396; https://doi.org/10.3390/inorganics11100396 - 9 Oct 2023

Cited by 1 | Viewed by 1379

Abstract

Four ligands based on the 2-tert-butyl-4-X-6-{Bis[(6-methoxy-pyridin-2-ylmethyl)-amino]-methyl}-phenol unit are synthesized: X = CHO (HL^CHO), putrescine-pyrene (HL^pyr), putrescine (HL^amine), and 2-tert-butyl-4-putrescine-6-{Bis[(6-methoxy-pyridin-2-ylmethyl)-amino]-methyl}-phenol (H₂L^bis). Complexes 1, 2, 3, and 4 are [...] Read more.

Four ligands based on the 2-tert-butyl-4-X-6-{Bis[(6-methoxy-pyridin-2-ylmethyl)-amino]-methyl}-phenol unit are synthesized: X = CHO (HL^CHO), putrescine-pyrene (HL^pyr), putrescine (HL^amine), and 2-tert-butyl-4-putrescine-6-{Bis[(6-methoxy-pyridin-2-ylmethyl)-amino]-methyl}-phenol (H₂L^bis). Complexes 1, 2, 3, and 4 are formed upon chelation to copper(II). The crystal structure of complex 1 shows a square pyramidal copper center with a very weakly bound methoxypridine moiety in the apical position. The pKa of the phenol moiety is determined spectrophotometrically at 2.82–4.39. All the complexes show a metal-centered reduction in their CV at E_p^c,red = −0.45 to −0.5 V vs. SCE. The copper complexes are efficient nucleases towards the ϕX174 DNA plasmid in the presence of ascorbate. The corresponding IC₅₀ value reaches 7 μM for 2, with a nuclease activity that follows the trend: 2 > 3 > 1. Strand scission is promoted by the hydroxyl radical. The cytotoxicity is evaluated on bladder cancer cell lines sensitive (RT112) or resistant to cisplatin (RT112 CP). The IC₅₀ of the most active complexes (2 and 4) is 1.2 and 1.0 μM, respectively, for the RT112 CP line, which is much lower than cisplatin (23.8 μM). Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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18 pages, 4384 KiB

Open AccessArticle

Copper(I)/Triphenylphosphine Complexes Containing Naphthoquinone Ligands as Potential Anticancer Agents

by Celisnolia M. Leite, João H. Araujo-Neto, Adriana P. M. Guedes, Analu R. Costa, Felipe C. Demidoff, Chaquip D. Netto, Eduardo E. Castellano, Otaciro R. Nascimento and Alzir A. Batista

Inorganics 2023, 11(9), 367; https://doi.org/10.3390/inorganics11090367 - 9 Sep 2023

Cited by 2 | Viewed by 1885

Abstract

Four new Cu/PPh₃/naphtoquinone complexes were synthesized, characterized (IR, UV/visible, 1D/2D NMR, mass spectrometry, elemental analysis, and X-ray diffraction), and evaluated as anticancer agents. We also investigated the reactive oxygen species (ROS) generation capacity of complex 4, considering the well-established photochemical [...] Read more.

Four new Cu/PPh₃/naphtoquinone complexes were synthesized, characterized (IR, UV/visible, 1D/2D NMR, mass spectrometry, elemental analysis, and X-ray diffraction), and evaluated as anticancer agents. We also investigated the reactive oxygen species (ROS) generation capacity of complex 4, considering the well-established photochemical property of naphthoquinones. Therefore, employing the electron paramagnetic resonance (EPR) “spin trap”, 5,5-dimethyl-1-pyrroline N-oxide (DMPO) technique, we identified the formation of the characteristic •OOH species (hydroperoxyl radical) adduct even before irradiating the solution containing complex 4. As the irradiation progressed, this radical species gradually diminished, primarily giving rise to a novel species known as •DMPO-OH (DMPO + •OH radical). These findings strongly suggest that Cu(I)/PPh₃/naphthoquinone complexes can generate ROS, even in the absence of irradiation, potentially intensifying their cytotoxic effect on tumor cells. Interpretation of the in vitro cytotoxicity data of the Cu(I) complexes considered their stability in cell culture medium. All of the complexes were cytotoxic to the lung (A549) and breast tumor cell lines (MDA-MB-231 and MCF-7). However, the higher toxicity for the lung (MRC5) and breast (MCF-10A) non-tumoral cells resulted in a low selectivity index. The morphological analysis of MDA-MB-231 cells treated with the complexes showed that they could cause decreased cell density, loss of cell morphology, and loss of cell adhesion, mainly with concentrations higher than the inhibitory concentration of 50% of cell viability (IC₅₀) values. Similarly, the clonogenic survivance of these cells was affected only with concentrations higher than the IC₅₀ values. An antimigratory effect was observed for complexes 1 and 4, showing around 20–40% of inhibition of wound closure in the wound healing experiments. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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15 pages, 3007 KiB

Open AccessArticle

Symmetrical and Unsymmetrical Dicopper Complexes Based on Bis-Oxazoline Units: Synthesis, Spectroscopic Properties and Reactivity

by James A. Isaac, Gisèle Gellon, Florian Molton, Christian Philouze, Nicolas Le Poul, Catherine Belle and Aurore Thibon-Pourret

Inorganics 2023, 11(8), 332; https://doi.org/10.3390/inorganics11080332 - 11 Aug 2023

Cited by 1 | Viewed by 1435

Abstract

Copper–oxygen adducts are known for being key active species for the oxidation of C–H bonds in copper enzymes and their synthetic models. In this work, the synthesis and spectroscopic characterizations of such intermediates using dinucleating ligands based on a 1,8 naphthyridine spacer with [...] Read more.

Copper–oxygen adducts are known for being key active species for the oxidation of C–H bonds in copper enzymes and their synthetic models. In this work, the synthesis and spectroscopic characterizations of such intermediates using dinucleating ligands based on a 1,8 naphthyridine spacer with oxazolines or mixed pyridine-oxazoline coordination moieties as binding pockets for copper ions have been explored. On the one hand, the reaction of dicopper(I) complexes with O₂ at low temperature led to the formation of a µ-η²:η² Cu₂:O₂ peroxido species according to UV-Vis spectroscopy monitoring. The reaction of these species with 2,4-di-tert-butyl-phenolate resulted in the formation of the C–C coupling product, but no insertion of oxygen occurred. On the other hand, the synthesis of dinuclear Cu(II) bis-µ-hydroxido complexes based on pyridine–oxazoline and oxazoline ligands were carried out to further generate Cu^IICu^III oxygen species. For both complexes, a reversible monoelectronic oxidation was detected via cyclic voltammetry at E_1/2 = 1.27 and 1.09 V vs. Fc⁺/Fc, respectively. Electron paramagnetic resonance spectroscopy (EPR) and UV-Vis spectroelectrochemical methods indicated the formation of a mixed-valent Cu^IICu^III species. Although no reactivity towards exogeneous substrates (toluene) could be observed, the Cu^IICu^III complexes were shown to be able to perform hydroxylation on the methyl group of the oxazoline moieties. The present study therefore indicates that the electrochemically generated Cu^IICu^III species described herein are capable of intramolecular aliphatic oxidation of C–H bonds. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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21 pages, 9382 KiB

Open AccessArticle

Copper(II) and Platinum(II) Naproxenates: Insights on Synthesis, Characterization and Evaluation of Their Antiproliferative Activities

by Amanda A. Silva, Silmara C. L. Frajácomo, Állefe B. Cruz, Kaio Eduardo Buglio, Daniele Daiane Affonso, Marcelo Cecconi Portes, Ana Lúcia T. G. Ruiz, João Ernesto de Carvalho, Wilton R. Lustri, Douglas H. Pereira, Ana M. da Costa Ferreira and Pedro P. Corbi

Inorganics 2023, 11(8), 331; https://doi.org/10.3390/inorganics11080331 - 10 Aug 2023

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Abstract

The growth of antibiotic resistance is a matter of worldwide concern. In parallel, cancer remains one of the main causes of death. In the search for new and improved antiproliferative agents, one of the strategies is the combination of bioactive ligands and metals [...] Read more.

The growth of antibiotic resistance is a matter of worldwide concern. In parallel, cancer remains one of the main causes of death. In the search for new and improved antiproliferative agents, one of the strategies is the combination of bioactive ligands and metals that are already consolidated in the synthesis of metallopharmaceutical agents. Thus, this work deals with the synthesis, characterization, and study of naproxen (Nap)-based complexes of copper(II) and platinum(II) as antiproliferative agents. The copper complex (Cu–Nap) presents a binuclear paddle-wheel structure in a 1 Cu:2 Nap:1 H₂O molar composition, in which Cu(II) is bonded to the carboxylate oxygens from naproxenate in a bidentate bridging mode. The platinum complex (Pt–Nap) was identified as the square planar cis-[Pt(Nap)₂(DMSO)₂] isomer, in which Pt(II) is bonded to the carboxylate oxygen atom of Nap in a monodentate fashion. Both complexes were inactive against the Gram-positive and Gram-negative bacterial strains assessed. Pt–Nap presented low cytostatic behavior over a set of tumor cells, but good viability for normal cells, while Cu–Nap was cytotoxic against all cells, with a cytocidal activity against glioma tumor cells. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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15 pages, 4673 KiB

Open AccessArticle

Oxidation of Phospholipids by OH Radical Coordinated to Copper Amyloid-β Peptide—A Density Functional Theory Modeling

by Alberto Rovetta, Laura Carosella, Federica Arrigoni, Jacopo Vertemara, Luca De Gioia, Giuseppe Zampella and Luca Bertini

Inorganics 2023, 11(6), 227; https://doi.org/10.3390/inorganics11060227 - 25 May 2023

Cited by 3 | Viewed by 1531

Abstract

Oxidative stress and metal dyshomeostasis are considered crucial factors in the pathogenesis of Alzheimer’s disease (AD). Indeed, transition metal ions such as Cu(II) can generate reactive oxygen species (ROS) via O₂ Fenton-like reduction, catalyzed by Cu(II) coordinated to the amyloid-beta (Aβ) peptide. [...] Read more.

Oxidative stress and metal dyshomeostasis are considered crucial factors in the pathogenesis of Alzheimer’s disease (AD). Indeed, transition metal ions such as Cu(II) can generate reactive oxygen species (ROS) via O₂ Fenton-like reduction, catalyzed by Cu(II) coordinated to the amyloid-beta (Aβ) peptide. Despite intensive efforts, the mechanisms of ROS-induced molecular damage remain poorly understood. In the present paper, we investigate, on the basis of Density Functional Theory (DFT) computations, a possible mechanism of the OH radical propagation toward membrane phospholipid polar head and fatty acid chains starting from the end-product of the OH radical generation by Cu(II)-Aβ. Using phosphatidylcholine as a model of a single unit inside a membrane, we evaluated the thermochemistry of the OH propagation with the oxidation of a C-H bond and the formation of the radical moiety. The DFT results show that Cu(II)-Aβ-OH can oxidize only sn-2 C-H bonds of the polar head and can easily oxidize the C-H bond adjacent to the carbon–carbon double bond in a mono or bis unsaturated fatty acid chain. These results are discussed on the basis of the recent literature on in vitro Aβ metal-catalyzed oxidation and on the possible implications in the AD oxidative stress mechanism. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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17 pages, 2159 KiB

Open AccessArticle

Novel Copper(II) Complexes with N⁴,S-Diallylisothiosemicarbazones as Potential Antibacterial/Anticancer Drugs

by Vasilii Graur, Irina Usataia, Ianina Graur, Olga Garbuz, Paulina Bourosh, Victor Kravtsov, Carolina Lozan-Tirsu, Greta Balan, Valeriu Fala and Aurelian Gulea

Inorganics 2023, 11(5), 195; https://doi.org/10.3390/inorganics11050195 - 30 Apr 2023

Cited by 4 | Viewed by 1815

Abstract

The six new copper(II) coordination compounds [Cu(HL¹)Cl₂] (1), [Cu(HL¹)Br₂] (2), [Cu(H₂O)(L¹)(CH₃COO)]·1.75H₂O (3), [Cu(HL²)Cl₂] (4), [Cu(HL [...] Read more.

The six new copper(II) coordination compounds [Cu(HL¹)Cl₂] (1), [Cu(HL¹)Br₂] (2), [Cu(H₂O)(L¹)(CH₃COO)]·1.75H₂O (3), [Cu(HL²)Cl₂] (4), [Cu(HL²)Br₂] (5), [Cu(H₂O)(L²)(CH₃COO)] (6) were synthesized with 2-formyl- and 2-acetylpyridine N⁴,S-diallylisothiosemicarbazones (HL¹ and HL²). The new isothiosemicarbazones were characterized by NMR, FTIR spectroscopy, and X-ray crystallography ([H₂L²]I). All copper(II) coordination compounds were characterized by elemental analysis, FTIR spectroscopy, and molar conductivity of their 1mM methanol solutions. Furthermore, the crystal structure of complex 3 was determined using single-crystal X-ray diffraction analysis. The studied complexes manifest antibacterial and antifungal activities, that in many cases are close to the activity of medical drugs used in this area, and in some cases even exceed them. The complexes 4 and 5 showed the highest indexes of selectivity (280 and 154) and high antiproliferative activity against BxPC-3 cell lines that surpass the activity of Doxorubicin. The complexes 1–3 also manifest antioxidant activities against cation radicals ABTS^•+ that are close to that of trolox, the antioxidant agent used in medicine. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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7 pages, 1295 KiB

Open AccessCommunication

Evaluation of Membrane Permeability of Copper-Based Drugs

by Evariste Umba-Tsumbu, Ahmed N. Hammouda and Graham Ellis Jackson

Inorganics 2023, 11(5), 179; https://doi.org/10.3390/inorganics11050179 - 23 Apr 2023

Cited by 1 | Viewed by 1682

Abstract

Membrane permeability of copper complexes with potential anti-inflammatory activity were measured using an artificial membrane in a modified Franz cell. Using CuCl₂ as the control, all the ligands tested enhanced the diffusion of copper, with enhancement factors ranging from 2 to 7. [...] Read more.

Membrane permeability of copper complexes with potential anti-inflammatory activity were measured using an artificial membrane in a modified Franz cell. Using CuCl₂ as the control, all the ligands tested enhanced the diffusion of copper, with enhancement factors ranging from 2 to 7. Octanol/water partition coefficients (log K_o/w) were measured and correlated with the permeability coefficients (K_p). In addition, chemical speciation was used to determine the predominant complex in solution at physiological pH. No correlation was found between the measured permeability coefficients and either molecular weight (MW) or log K_o/w. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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Review

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23 pages, 3440 KiB

Open AccessEditor’s ChoiceReview

The Importance of Being Casiopeina as Polypharmacologycal Profile (Mixed Chelate–Copper (II) Complexes and Their In Vitro and In Vivo Activities)

by Zenayda Aguilar-Jiménez, Adrián Espinoza-Guillén, Karen Resendiz-Acevedo, Inés Fuentes-Noriega, Carmen Mejía and Lena Ruiz-Azuara

Inorganics 2023, 11(10), 394; https://doi.org/10.3390/inorganics11100394 - 7 Oct 2023

Cited by 15 | Viewed by 3055

Abstract

In this review, we present a timeline that shows the origin of mixed chelate copper (II) complexes, registered as Mark Title Casiopeínas^®, as the first copper (II) compounds proposed as anticancer drugs in 1988 and 1992. In the late twentieth century, [...] Read more.

In this review, we present a timeline that shows the origin of mixed chelate copper (II) complexes, registered as Mark Title Casiopeínas^®, as the first copper (II) compounds proposed as anticancer drugs in 1988 and 1992. In the late twentieth century, the use of essential metals as anticancer agents was not even considered, except for their antifungal or antibacterial effects; also, copper, as gold salts, was used for arthritis problems. The use of essential metals as anticancer drugs to diminish the secondary toxic effects of Cisplatin was our driving force: to find less toxic and even more economical compounds under the rational design of metal chelate complexes. Due to their chemical properties, copper compounds were the choice to continue anticancer drug development. In this order of ideas, the rational designs of mixed chelate–copper (II) complexes (Casiopeínas, (Cas) homoleptic or heteroleptic, depending on the nature of the secondary ligand) were synthesized and fully characterized. In the search for new, more effective, and less toxic drugs, Casiopeína^® (Cas) emerged as a family of approximately 100 compounds synthesized from coordinated Cu(II) complexes with proven antineoplastic potential through cytotoxic action. The Cas have the general formula [Cu(N–N)(N–O)]NO₃ and [Cu(N–N)(O–O)]NO₃, where N–N is an aromatic substituted diimine (1,10-phenanthroline or 2,2′-bipyridine), and the oxygen donor (O–O) is acetylacetonate or salicylaldehyde. Lately, some similar compounds have been developed by other research groups considering a similar hypothesis after Casiopeína’s discoveries had been published, as described herein. As an example of translational medicine criteria, we have covered each step of the established normative process for drug development, and consequently, one of the molecules (Casiopeína III ia (CasIIIia)) has reached the clinical phase I. For these copper compounds, other activities, such as antibacterial, antiparasitic and antiviral, have been discovered. Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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13 pages, 2009 KiB

Open AccessReview

Probing the Bioinorganic Chemistry of Cu(I) with ¹¹¹Ag Perturbed Angular Correlation (PAC) Spectroscopy

by Victoria Karner, Attila Jancso and Lars Hemmingsen

Inorganics 2023, 11(10), 375; https://doi.org/10.3390/inorganics11100375 - 23 Sep 2023

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Abstract

The two most common oxidation states of copper in biochemistry are Cu(II) and Cu(I), and while Cu(II) lends itself to spectroscopic interrogation, Cu(I) is silent in most techniques. Ag(I) and Cu(I) are both closed-shell d¹⁰ monovalent ions, and to some extent share [...] Read more.

The two most common oxidation states of copper in biochemistry are Cu(II) and Cu(I), and while Cu(II) lends itself to spectroscopic interrogation, Cu(I) is silent in most techniques. Ag(I) and Cu(I) are both closed-shell d¹⁰ monovalent ions, and to some extent share ligand and coordination geometry preferences. Therefore, Ag(I) may be applied to explore Cu(I) binding sites in biomolecules. Here, we review applications of ¹¹¹Ag perturbed angular correlation (PAC) of γ-ray spectroscopy aimed to elucidate the chemistry of Cu(I) in biological systems. Examples span from small blue copper proteins such as plastocyanin and azurin (electron transport) over hemocyanin (oxygen transport) to CueR and BxmR (metal-ion-sensing proteins). Finally, possible future applications are discussed. ¹¹¹Ag is a radionuclide which undergoes β-decay to ¹¹¹Cd, and it is a γ-γ cascade of the ¹¹¹Cd daughter nucleus, which is used in PAC measurements. ¹¹¹Ag PAC spectroscopy may provide information on the coordination environment of Ag(I) and on the structural relaxation occurring upon the essentially instantaneous change from Ag(I) to Cd(II). Full article

(This article belongs to the Special Issue Editorial Board Members’ Collection Series in “Bioinorganic Chemistry of Copper”)

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