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29 pages, 8254 KiB

Open AccessArticle

The Role of Side Chains in the Fine-Tuning of the Metal-Binding Ability of Multihistidine Peptides

by Enikő Székely, Gizella Csire, Bettina Diána Balogh, Judit Zsuzsa Erdei, Judit Mária Király, Judit Kocsi, Júlia Pinkóczy and Katalin Várnagy

Molecules 2022, 27(11), 3435; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27113435 - 26 May 2022

Cited by 4 | Viewed by 1597

Abstract

The systematic studies of copper(II), nickel(II) and zinc(II) ion complexes of protected multihistidine peptides containing amino acids with different side chains (Ac-SarHAH-NH₂, Ac-HADH-NH₂, Ac-HDAH-NH₂, Ac-HXHYH-NH₂ X, Y = A, F, D or K, Ac-HXHAHXH-NH₂, [...] Read more.

The systematic studies of copper(II), nickel(II) and zinc(II) ion complexes of protected multihistidine peptides containing amino acids with different side chains (Ac-SarHAH-NH₂, Ac-HADH-NH₂, Ac-HDAH-NH₂, Ac-HXHYH-NH₂ X, Y = A, F, D or K, Ac-HXHAHXH-NH₂, X = F or D) have provided information about the metal ion and protein interaction and have made it possible to draw conclusions regarding general trends in the coordination of metal complexes of multihistidine peptides. The stability of the metal complexes significantly depends on the position of the histidines and amino acids, which are present in the neighbourhood of the histidine amino acids as well. The most significant effect was observed on peptides containing aspartic acid or phenylalanine. The redox parameters of complexes, however, depend on the number and position of histidines, and the other side chain donor atoms have practically no effect on the electrochemical properties of imidazole-coordinated species. However, the presence of aspartic acid side chains results in a more distorted geometry of amide-coordinated species and increases the reducibility of these complexes. Full article

(This article belongs to the Special Issue New Insights into Metal Complexes of Amino Acids and Peptides: Chemistry and Application)

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15 pages, 2478 KiB

Open AccessFeature PaperArticle

Hybrid Bis-Histidine Phenanthroline-Based Ligands to Lessen Aβ-Bound Cu ROS Production: An Illustration of Cu(I) Significance

by Marielle Drommi, Clément Rulmont, Charlène Esmieu and Christelle Hureau

Molecules 2021, 26(24), 7630; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26247630 - 16 Dec 2021

Cited by 6 | Viewed by 2416

Abstract

We here report the synthesis of three new hybrid ligands built around the phenanthroline scaffold and encompassing two histidine-like moieties: phenHH, phenHGH and H’phenH’, where H correspond to histidine and H’ to histamine. These ligands were designed to capture Cu(I/II) from the amyloid-β [...] Read more.

We here report the synthesis of three new hybrid ligands built around the phenanthroline scaffold and encompassing two histidine-like moieties: phenHH, phenHGH and H’phenH’, where H correspond to histidine and H’ to histamine. These ligands were designed to capture Cu(I/II) from the amyloid-β peptide and to prevent the formation of reactive oxygen species produced by amyloid-β bound copper in presence of physiological reductant (e.g., ascorbate) and dioxygen. The amyloid-β peptide is a well-known key player in Alzheimer’s disease, a debilitating and devasting neurological disorder the mankind has to fight against. The Cu-Aβ complex does participate in the oxidative stress observed in the disease, due to the redox ability of the Cu(I/II) ions. The complete characterization of the copper complexes made with phenHH, phenHGH and H’phenH’ is reported, along with the ability of ligands to remove Cu from Aβ, and to prevent the formation of reactive oxygen species catalyzed by Cu and Cu-Aβ, including in presence of zinc, the second metal ions important in the etiology of Alzheimer’s disease. The importance of the reduced state of copper, Cu(I), in the prevention and arrest of ROS is mechanistically described with the help of cyclic voltammetry experiments. Full article

(This article belongs to the Special Issue New Insights into Metal Complexes of Amino Acids and Peptides: Chemistry and Application)

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20 pages, 3290 KiB

Open AccessArticle

Comparative Study of Antioxidant and Pro-Oxidant Properties of Homoleptic and Heteroleptic Copper Complexes with Amino Acids, Dipeptides and 1,10-Phenanthroline: The Quest for Antitumor Compounds

by Nicolás Veiga, Natalia Alvarez, Eduardo E. Castellano, Javier Ellena, Gianella Facchin and María H. Torre

Molecules 2021, 26(21), 6520; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216520 - 28 Oct 2021

Cited by 8 | Viewed by 1830

Abstract

In a search for new antitumoral agents, a series of homoleptic copper(II) complexes with amino acids and dipeptides, as well as heteroleptic complexes containing both dipeptides and 1,10-phenanthroline, were studied. Furthermore, a single-crystal structure containing alanyl-leucinato ([Cu₃(AlaLeu)₃(H₂O) [...] Read more.

In a search for new antitumoral agents, a series of homoleptic copper(II) complexes with amino acids and dipeptides, as well as heteroleptic complexes containing both dipeptides and 1,10-phenanthroline, were studied. Furthermore, a single-crystal structure containing alanyl-leucinato ([Cu₃(AlaLeu)₃(H₂O)₃(CO₃)]·PF₆·H₂O), which is the first homotrinuclear carbonato-bridged copper(II) complex with a dipeptide moiety, is presented. To assess possible antitumor action mechanisms, we focused on the comparative analysis of pro- and antioxidant behaviors. Pro-oxidant activity, in which the reactive oxygen species (ROS) formed by the reaction of the complexes with H₂O₂ produce oxidative damage to 2-deoxy-d-ribose, was evaluated using the TBARS method. Additionally, the antioxidant action was quantified through the superoxide dismutase (SOD)-like activity, using a protocol based on the inhibitory effect of SOD on the reduction of nitrobluetetrazolium (NBT) by the superoxide anion generated by the xanthine/xanthine oxidase system. Our findings show that Cu–amino acid complexes are strong ROS producers and moderate SOD mimics. Conversely, Cu–dipeptide–phen complexes are good SOD mimics but poor ROS producers. The activity of Cu–dipeptide complexes was strongly dependent on the dipeptide. A DFT computational analysis revealed that complexes with high SOD-like activity tend to display a large dipole moment and condensed-to-copper charge, softness and LUMO contribution. Moreover, good ROS producers have higher global hardness and copper electrophilicity, lower copper softness and flexible and freely accessible coordination polyhedra. Full article

(This article belongs to the Special Issue New Insights into Metal Complexes of Amino Acids and Peptides: Chemistry and Application)

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27 pages, 5079 KiB

Open AccessArticle

Antimicrobial and Anticancer Application of Silver(I) Dipeptide Complexes

by Gabriela Kuzderová, Michaela Rendošová, Róbert Gyepes, Simona Sovová, Danica Sabolová, Mária Vilková, Petra Olejníková, Ivana Bačová, Simonida Stokič, Martin Kello and Zuzana Vargová

Molecules 2021, 26(21), 6335; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26216335 - 20 Oct 2021

Cited by 5 | Viewed by 2225

Abstract

Three silver(I) dipeptide complexes [Ag(GlyGly)]_n(NO₃)_n (AgGlyGly), [Ag₂(GlyAla)(NO₃)₂]_n (AgGlyAla) and [Ag₂(HGlyAsp)(NO₃)]_n (AgGlyAsp) were prepared, investigated and characterized by vibrational spectroscopy (mid-IR), elemental and thermogravimetric analysis and mass [...] Read more.

Three silver(I) dipeptide complexes [Ag(GlyGly)]_n(NO₃)_n (AgGlyGly), [Ag₂(GlyAla)(NO₃)₂]_n (AgGlyAla) and [Ag₂(HGlyAsp)(NO₃)]_n (AgGlyAsp) were prepared, investigated and characterized by vibrational spectroscopy (mid-IR), elemental and thermogravimetric analysis and mass spectrometry. For AgGlyGly, X-ray crystallography was also performed. Their stability in biological testing media was verified by time-dependent NMR measurements. Their in vitro antimicrobial activity was evaluated against selected pathogenic microorganisms. Moreover, the influence of silver(I) dipeptide complexes on microbial film formation was described. Further, the cytotoxicity of the complexes against selected cancer cells (BLM, MDA-MB-231, HeLa, HCT116, MCF-7 and Jurkat) and fibroblasts (BJ-5ta) using a colorimetric MTS assay was tested, and the selectivity index (SI) was identified. The mechanism of action of Ag(I) dipeptide complexes was elucidated and discussed by the study in terms of their binding affinity toward the CT DNA, the ability to cleave the DNA and the ability to influence numbers of cells within each cell cycle phase. The new silver(I) dipeptide complexes are able to bind into DNA by noncovalent interaction, and the topoisomerase I inhibition study showed that the studied complexes inhibit its activity at a concentration of 15 μM. Full article

(This article belongs to the Special Issue New Insights into Metal Complexes of Amino Acids and Peptides: Chemistry and Application)

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20 pages, 2152 KiB

Open AccessArticle

Synthesis, Characterization, and Reaction Studies of Pd(II) Tripeptide Complexes

by Lindsey J. Monger, Dmitrii Razinkov, Ragnar Bjornsson and Sigridur G. Suman

Molecules 2021, 26(17), 5169; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26175169 - 26 Aug 2021

Cited by 4 | Viewed by 2475

Abstract

The aqueous synthesis of Pd(II) complexes with alkylated tripeptides led to the hydrolysis of the peptides at low pH values and mixtures of complexed peptides were formed. A non-aqueous synthetic route allowed the formation and isolation of single products and their characterization. Pd(II) [...] Read more.

The aqueous synthesis of Pd(II) complexes with alkylated tripeptides led to the hydrolysis of the peptides at low pH values and mixtures of complexed peptides were formed. A non-aqueous synthetic route allowed the formation and isolation of single products and their characterization. Pd(II) complexes with α-Asp(OR)AlaGly(OR), β-Asp(OR)AlaGly(OR), and TrpAlaGly(OR) (R = H or alkyl) as tri and tetradentate chelates were characterized. The tridentate coordination mode was accompanied by a fourth monodentate ligand that was shown to participate in both ligand exchange reactions and a direct removal to form the tetradentate coordination mode. The tetradentate coordination revealed a rare a hemi labile carbonyl goup coordination mode to Pd(II). Reactivity with small molecules such as ethylene, acids, formate, and episulfide was investigated. Under acidic conditions and in the presence of ethylene; acetaldehyde was formed. The Pd(II) is a soft Lewis acid and thiophilic and the complexes abstract sulfur from episulfide at apparent modest catalytic rates. The complexes adopt a square planar geometry according to a spectroscopic analysis and DFT calculations that were employed to evaluate the most energetically favorable coordination geometry and compared with the observed infrared and NMR data. Full article

(This article belongs to the Special Issue New Insights into Metal Complexes of Amino Acids and Peptides: Chemistry and Application)

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15 pages, 5507 KiB

Open AccessArticle

Binding Models of Copper(II) Thiosemicarbazone Complexes with Human Serum Albumin: A Speciation Study

by Nóra V. May, Attila Jancsó and Éva A. Enyedy

Molecules 2021, 26(9), 2711; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092711 - 05 May 2021

Cited by 10 | Viewed by 2874

Abstract

Copper(II) complexes of thiosemicarbazones (TSCs) often exhibit anticancer properties, and their pharmacokinetic behavior can be affected by their interaction with blood transport proteins. Interaction of copper(II) complexes of an {N,N,S} donor α-N-pyridyl TSC (Triapine) and an {O,N,S} donor 2-hydroxybenzaldehyde TSC (STSC) [...] Read more.

Copper(II) complexes of thiosemicarbazones (TSCs) often exhibit anticancer properties, and their pharmacokinetic behavior can be affected by their interaction with blood transport proteins. Interaction of copper(II) complexes of an {N,N,S} donor α-N-pyridyl TSC (Triapine) and an {O,N,S} donor 2-hydroxybenzaldehyde TSC (STSC) with human serum albumin (HSA) was investigated by UV–visible and electron paramagnetic resonance spectroscopy at physiological pH. Asp-Ala-His-Lys and the monodentate N-methylimidazole were also applied as binding models. Conditional formation constants were determined for the ternary copper(II)-TSC complexes formed with HSA, DAHK, and N-methylimidazole based on the spectral changes of both charge transfer and d-d bands. The neutral N-methylimidazole displays a similar binding affinity to both TSC complexes. The partially negatively charged tetrapeptide binds stronger to the positively charged Triapine complex in comparison to the neutral STSC complex, while the opposite trend was observed for HSA, which demonstrates the limitations of the use of simple ligands to model the protein binding. The studied TSC complexes are able to bind to HSA in a fast process, and the conditional constants suggest that their binding strength is only weak-to-moderate. Full article

(This article belongs to the Special Issue New Insights into Metal Complexes of Amino Acids and Peptides: Chemistry and Application)

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14 pages, 2727 KiB

Open AccessArticle

Synthesis and Chemical and Biological Evaluation of a Glycine Tripeptide Chelate of Magnesium

by Derek R. Case, Jon Zubieta, Ren Gonzalez and Robert P. Doyle

Molecules 2021, 26(9), 2419; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092419 - 21 Apr 2021

Cited by 6 | Viewed by 3501

Abstract

Magnesium (Mg²⁺) plays a crucial role in over 80% of all metabolic functions. It is becoming increasingly apparent that magnesium deficiency (hypomagnesemia) may play an important role in chronic disease. To counteract magnesium deficiency, there is an unmet clinical need to [...] Read more.

Magnesium (Mg²⁺) plays a crucial role in over 80% of all metabolic functions. It is becoming increasingly apparent that magnesium deficiency (hypomagnesemia) may play an important role in chronic disease. To counteract magnesium deficiency, there is an unmet clinical need to develop new fully characterized, highly bioavailable, and substantially water-soluble magnesium supplements. To this end, triglycine (HG₃), a tripeptide of the amino acid glycine, was chosen as a chelating ligand for magnesium, given its natural occurrence and water solubility, and entropically-driven metal binding. Herein, we discuss the synthesis, chemical and physical characterization, and cellular uptake of a magnesium triglycine chelate (MgG₃), an octahedral complex with extraordinary water solubility and improved cellular uptake in CaCo-2 cells than select commonly used magnesium supplements. Full article

(This article belongs to the Special Issue New Insights into Metal Complexes of Amino Acids and Peptides: Chemistry and Application)

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Review

Jump to: Research

19 pages, 1647 KiB

Open AccessReview

Aβ and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer’s Disease?

by Giuseppe Di Natale, Giuseppina Sabatino, Michele Francesco Maria Sciacca, Rita Tosto, Danilo Milardi and Giuseppe Pappalardo

Molecules 2022, 27(16), 5066; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27165066 - 09 Aug 2022

Cited by 15 | Viewed by 2957

Abstract

In the last two decades, the amyloid hypothesis, i.e., the abnormal accumulation of toxic Aβ assemblies in the brain, has been considered the mainstream concept sustaining research in Alzheimer’s Disease (AD). However, the course of cognitive decline and AD development better correlates with [...] Read more.

In the last two decades, the amyloid hypothesis, i.e., the abnormal accumulation of toxic Aβ assemblies in the brain, has been considered the mainstream concept sustaining research in Alzheimer’s Disease (AD). However, the course of cognitive decline and AD development better correlates with tau accumulation rather than amyloid peptide deposition. Moreover, all clinical trials of amyloid-targeting drug candidates have been unsuccessful, implicitly suggesting that the amyloid hypothesis needs significant amendments. Accumulating evidence supports the existence of a series of potentially dangerous relationships between Aβ oligomeric species and tau protein in AD. However, the molecular determinants underlying pathogenic Aβ/tau cross interactions are not fully understood. Here, we discuss the common features of Aβ and tau molecules, with special emphasis on: (i) the critical role played by metal dyshomeostasis in promoting both Aβ and tau aggregation and oxidative stress, in AD; (ii) the effects of lipid membranes on Aβ and tau (co)-aggregation at the membrane interface; (iii) the potential of small peptide-based inhibitors of Aβ and tau misfolding as therapeutic tools in AD. Although the molecular mechanism underlying the direct Aβ/tau interaction remains largely unknown, the arguments discussed in this review may help reinforcing the current view of a synergistic Aβ/tau molecular crosstalk in AD and stimulate further research to mechanism elucidation and next-generation AD therapeutics. Full article

(This article belongs to the Special Issue New Insights into Metal Complexes of Amino Acids and Peptides: Chemistry and Application)

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27 pages, 9146 KiB

Open AccessReview

Diversity in the Interaction of Amino Acid- and Peptide-Based Hydroxamic Acids with Some Platinum Group Metals in Solution

by Linda Bíró, Péter Buglyó and Etelka Farkas

Molecules 2022, 27(3), 669; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules27030669 - 20 Jan 2022

Cited by 4 | Viewed by 2427

Abstract

Complexes that incorporate both ligand(s) and metal(s) exhibiting cytotoxic activity can especially be interesting to develop multifunctional drug molecules with desired activities. In this review, the limited number of solution results collected in our laboratory on the complexes of Pd(II) and two other [...] Read more.

Complexes that incorporate both ligand(s) and metal(s) exhibiting cytotoxic activity can especially be interesting to develop multifunctional drug molecules with desired activities. In this review, the limited number of solution results collected in our laboratory on the complexes of Pd(II) and two other platinum group metals—the half-sandwich type, [(η⁶-p-cym)Ru(H₂O)₃]²⁺, and [(η⁵-Cp*)Rh(H₂O)₃]²⁺—with hydroxamic acid derivatives of three amino acids, two imidazole analogues, and four small peptides are summarized and evaluated. Unlike the limited number of coordination sites of these metal ions (four and three for Pd(II) and the organometallic cations, respectively), the ligands discussed here offer a relatively high number of donor atoms as well as variation in their position within the ligands, resulting in a large versatility of the likely coordination modes. The review, besides presenting the solution equilibrium results, also discusses the main factors, such as (N,N) versus (O,O) chelate; size of chelate; amino-N versus imidazole-N; primary versus secondary hydroxamic function; differences between hydrolytic ability of the metal ions studied; and hydrolysis of the coordinated peptide hydroxamic acids in their Pd(II) complexes, which all determine the coordination modes present in the complexes formed in measurable concentrations in these systems. The options for the quantitative evaluation of metal binding effectivity and selectivity of the various ligands and the comparison with each other by using solution equilibrium data are also discussed. Full article

(This article belongs to the Special Issue New Insights into Metal Complexes of Amino Acids and Peptides: Chemistry and Application)

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