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This review presents an overview of the biological applications of coordinative compounds based on unsaturated carboxylates accompanied by other ligands, usually N-based heterocyclic species. The interest in these compounds arises from the valuable antimicrobial and antitumor activities evidenced by some species, as well as from their ability to generate metal-containing polymers suitable for various medical purposes. Therefore, we describe the recently discovered aspects related to the synthesis, structure, and biological activity of a wide range of unsaturated carboxylate-containing species and metal ions, originating mostly from 3d series. The unsaturated carboxylates encountered in coordinative compounds are acrylate, methacrylate, fumarate, maleate, cinnamate, ferulate, coumarate, and itaconate. Regarding the properties of the investigated compounds, it is worth mentioning the good ability of some to inhibit the development of resistant strains or microbial biofilms on inert surfaces or, even more, exert antitumor activity against resistant cells. The ability of some species to intercalate into DNA strands as well as to scavenge ROS species is also addressed. [ABSTRACT FROM AUTHOR]

The widespread prevalence of infectious bacteria is one of the greatest threats to public health, and consequently, there is an urgent need for efficient and broad-spectrum antibacterial materials that are antibiotic-free. In this study, 2-pyridinecarboxaldehyde (PCA) was grafted onto chitosan (CS) and the modified CS coordinated with silver ions to prepare PCA-CS-Ag complexes with antibacterial activity. To obtain complexes with a high silver content, the preparation process was optimized using single-factor experiments and response surface methodology. Under the optimal preparation conditions (an additional amount of silver nitrate (58 mg), a solution pH of 3.9, and a reaction temperature of 69 °C), the silver content of the PCA-CS-Ag complex reached 13.27 mg/g. The structure of the PCA-CS-Ag complex was subsequently verified using ultraviolet–visible spectroscopy, Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and thermogravimetric analysis. Furthermore, three possible complexation modes of the PCA-CS-Ag complex were proposed using molecular mechanics calculations. The results of the antibacterial assay in vitro showed that the PCA-CS-Ag complex exhibited strong antibacterial activity against both Gram-positive and Gram-negative bacteria, exerting the synergistic antibacterial effect of modified chitosan and silver ions. Therefore, the PCA-CS-Ag complex is expected to be developed as an effective antibacterial material with promising applications in food films, packaging, medical dressings, and other fields. [ABSTRACT FROM AUTHOR]

This review presents an overview of the biological applications of coordinative compounds based on unsaturated carboxylates accompanied by other ligands, usually N-based heterocyclic species. The interest in these compounds arises from the valuable antimicrobial and antitumor activities evidenced by some species, as well as from their ability to generate metal-containing polymers suitable for various medical purposes. Therefore, we describe the recently discovered aspects related to the synthesis, structure, and biological activity of a wide range of unsaturated carboxylate-containing species and metal ions, originating mostly from 3d series. The unsaturated carboxylates encountered in coordinative compounds are acrylate, methacrylate, fumarate, maleate, cinnamate, ferulate, coumarate, and itaconate. Regarding the properties of the investigated compounds, it is worth mentioning the good ability of some to inhibit the development of resistant strains or microbial biofilms on inert surfaces or, even more, exert antitumor activity against resistant cells. The ability of some species to intercalate into DNA strands as well as to scavenge ROS species is also addressed.

The pH-dependent binding strengths and modes of the organometallic [(η6-p-cym)M(H2O)3]2+ (MII = Ru, Os; p-cym = 1-methyl-4-isopropylbenzene) or [(η5-Cp*)M(H2O)3]2+ (MIII = Rh, Ir; Cp* = pentamethylcyclopentadienyl anion) cations towards iminodiacetic acid (H2Ida) and its biorelevant mono- and diphosphonate derivatives N-(phosphonomethyl)-glycine (H3IdaP) and iminodi(methylphosphonic acid) (H4Ida2P) was studied in an aqueous solution. The results showed that all three of the ligands form 1:1 complexes via the tridentate (O,N,O) donor set, for which the binding mode was further corroborated by the DFT method. Although with IdaP3− and Ida2P4− in mono- and bis-protonated species, where H+ might also be located at the non-coordinating N atom, the theoretical calculations revealed the protonation of the phosphonate group(s) and the tridentate coordination of the phosphonate ligands. The replacement of one carboxylate in Ida2− by a phosphonate group (IdaP3−) resulted in a significant increase in the stability of the metal complexes; however, this increase vanished with Ida2P4−, which was most likely due to some steric hindrance upon the coordination of the second large phosphonate group to form (5 + 5) joined chelates. In the phosphonate-containing systems, the neutral 1:1 complexes are the major species at pH 7.4 in the millimolar concentration range that is supported by both NMR and ESI-TOF-MS. [ABSTRACT FROM AUTHOR]

Rutin is a natural flavonoid that carries out a variety of biological activities, but its application in medicine and food is limited by its water solubility. One of the classical methods used to enhance drug solubility is encapsulation with cyclodextrins. In this paper, the encapsulation of different cyclodextrins with rutin was investigated using a combination of experimental and simulation methods. Three inclusions of rutin/beta-cyclodextrin (β-CD), rutin/2-hydroxypropyl beta-cyclodextrin (HP-β-CD) and rutin/2,6-dimethyl beta-cyclodextrin (DM-β-CD) were prepared by the freeze-drying method, and the inclusions were analyzed using Fourier infrared spectroscopy (FTIR), X-ray diffraction analysis (XRD), differential scanning calorimetry (DSC) and ultraviolet–visible spectroscopy (UV) to characterize and demonstrate the formation of the inclusion complexes. Phase solubility studies showed that rutin formed a 1:1 stoichiometric inclusion complex and significantly increased its solubility. β-CD, HP-β-CD, DM-β-CD, rutin and the three inclusion complexes were modeled by using MS2018 and AutoDock 4.0, and molecular dynamics simulations were performed to calculate the solubility parameters, binding energies, mean square displacement (MSD), hydrogen bonding and radial distribution functions (RDF) after the equilibration of the systems. The results of simulation and experiment showed that rutin/DM-β-CD had the best encapsulation effect among the three cyclodextrin inclusion complexes. [ABSTRACT FROM AUTHOR]

The widespread prevalence of infectious bacteria is one of the greatest threats to public health, and consequently, there is an urgent need for efficient and broad-spectrum antibacterial materials that are antibiotic-free. In this study, 2-pyridinecarboxaldehyde (PCA) was grafted onto chitosan (CS) and the modified CS coordinated with silver ions to prepare PCA-CS-Ag complexes with antibacterial activity. To obtain complexes with a high silver content, the preparation process was optimized using single-factor experiments and response surface methodology. Under the optimal preparation conditions (an additional amount of silver nitrate (58 mg), a solution pH of 3.9, and a reaction temperature of 69 °C), the silver content of the PCA-CS-Ag complex reached 13.27 mg/g. The structure of the PCA-CS-Ag complex was subsequently verified using ultraviolet–visible spectroscopy, Fourier-transform infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and thermogravimetric analysis. Furthermore, three possible complexation modes of the PCA-CS-Ag complex were proposed using molecular mechanics calculations. The results of the antibacterial assay in vitro showed that the PCA-CS-Ag complex exhibited strong antibacterial activity against both Gram-positive and Gram-negative bacteria, exerting the synergistic antibacterial effect of modified chitosan and silver ions. Therefore, the PCA-CS-Ag complex is expected to be developed as an effective antibacterial material with promising applications in food films, packaging, medical dressings, and other fields.

An efficient approach to the synthesis of diamides of 4,7-difluoro-1,10-phenanthroline-2,9-dicarboxylic acid was elaborated. Direct nucleophilic substitution with 4,7-dichloro-1,10-phenanthroline precursors opened access to difluoro derivatives in high yield. As a result, four new fluorinated ligands were prepared in up to 88% yield. Their structure was proved by a combination of spectral methods and X-ray data. A set of lanthanoid complexes was prepared to demonstrate the utility of new ligands. The structure of the complexes was studied in solid state (IR-spectroscopy, X-ray diffraction) and in solution (NMR-spectroscopy). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The pH-dependent binding strengths and modes of the organometallic [(η6-p-cym)M(H2O)3]2+ (MII = Ru, Os; p-cym = 1-methyl-4-isopropylbenzene) or [(η5-Cp*)M(H2O)3]2+ (MIII = Rh, Ir; Cp* = pentamethylcyclopentadienyl anion) cations towards iminodiacetic acid (H2Ida) and its biorelevant mono- and diphosphonate derivatives N-(phosphonomethyl)-glycine (H3IdaP) and iminodi(methylphosphonic acid) (H4Ida2P) was studied in an aqueous solution. The results showed that all three of the ligands form 1:1 complexes via the tridentate (O,N,O) donor set, for which the binding mode was further corroborated by the DFT method. Although with IdaP3− and Ida2P4− in mono- and bis-protonated species, where H+ might also be located at the non-coordinating N atom, the theoretical calculations revealed the protonation of the phosphonate group(s) and the tridentate coordination of the phosphonate ligands. The replacement of one carboxylate in Ida2− by a phosphonate group (IdaP3−) resulted in a significant increase in the stability of the metal complexes; however, this increase vanished with Ida2P4−, which was most likely due to some steric hindrance upon the coordination of the second large phosphonate group to form (5 + 5) joined chelates. In the phosphonate-containing systems, the neutral 1:1 complexes are the major species at pH 7.4 in the millimolar concentration range that is supported by both NMR and ESI-TOF-MS.

Rutin is a natural flavonoid that carries out a variety of biological activities, but its application in medicine and food is limited by its water solubility. One of the classical methods used to enhance drug solubility is encapsulation with cyclodextrins. In this paper, the encapsulation of different cyclodextrins with rutin was investigated using a combination of experimental and simulation methods. Three inclusions of rutin/beta-cyclodextrin (β-CD), rutin/2-hydroxypropyl beta-cyclodextrin (HP-β-CD) and rutin/2,6-dimethyl beta-cyclodextrin (DM-β-CD) were prepared by the freeze-drying method, and the inclusions were analyzed using Fourier infrared spectroscopy (FTIR), X-ray diffraction analysis (XRD), differential scanning calorimetry (DSC) and ultraviolet–visible spectroscopy (UV) to characterize and demonstrate the formation of the inclusion complexes. Phase solubility studies showed that rutin formed a 1:1 stoichiometric inclusion complex and significantly increased its solubility. β-CD, HP-β-CD, DM-β-CD, rutin and the three inclusion complexes were modeled by using MS2018 and AutoDock 4.0, and molecular dynamics simulations were performed to calculate the solubility parameters, binding energies, mean square displacement (MSD), hydrogen bonding and radial distribution functions (RDF) after the equilibration of the systems. The results of simulation and experiment showed that rutin/DM-β-CD had the best encapsulation effect among the three cyclodextrin inclusion complexes.

An efficient approach to the synthesis of diamides of 4,7-difluoro-1,10-phenanthroline-2,9-dicarboxylic acid was elaborated. Direct nucleophilic substitution with 4,7-dichloro-1,10-phenanthroline precursors opened access to difluoro derivatives in high yield. As a result, four new fluorinated ligands were prepared in up to 88% yield. Their structure was proved by a combination of spectral methods and X-ray data. A set of lanthanoid complexes was prepared to demonstrate the utility of new ligands. The structure of the complexes was studied in solid state (IR-spectroscopy, X-ray diffraction) and in solution (NMR-spectroscopy).

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.

Around 5% of the population of the world is affected with the disease called diabetes mellitus. The main medication of the diabetes is the insulin; the active form is the insulin monomer, which is an instable molecule, because the long storage time, or the high temperature, can cause the monomer insulin to adapt an alternative fold, rich in β-sheets, which is pharmaceutically inactive. The aim of this study is to form different insulin complexes with all the cyclodextrin used for pharmaceutical excipients (native cyclodextrin, methyl, hydroxyethyl, hydroxypropyl and sulfobutylether substituted β-cyclodextrin), in silico condition, with the AutoDock molecular modeling program, to determine the best type of cyclodextrin or cyclodextrin derivate to form a complex with an insulin monomer, to predict the molar ratio, the conformation of the complex, and the intermolecular hydrogen bonds formed between the cyclodextrin and the insulin. From the results calculated by the AutoDock program it can be predicted that insulin can make a stable complex with 5–7 molecules of hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin, and by forming a complex potentially can prevent or delay the amyloid fibrillation of the insulin and increase the stability of the molecule.

In an attempt to increase the biological activity of the 1,2,4-triazolo[1,5-a]pyrimidine scaffold through complexation with essential metal ions, the complexes trans-[Cu(mptp)2Cl2] (1), [Zn(mptp)Cl2(DMSO)] (2) (mptp: 5-methyl-7-phenyl-1,2,4-triazolo[1,5-a]pyrimidine), [Cu2(dmtp)4Cl4]·2H2O (3) and [Zn(dmtp)2Cl2] (4) (dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine), were synthesized and characterized as new antiproliferative and antimicrobial species. Both complexes (1) and (2) crystallize in the P21/n monoclinic space group, with the tetrahedral surroundings generating a square-planar stereochemistry in the Cu(II) complex and a tetrahedral stereochemistry in the Zn(II) species. The mononuclear units are interconnected in a supramolecular network through π–π interactions between the pyrimidine moiety and the phenyl ring in (1) while supramolecular chains resulting from C-H∙∙∙π interactions were observed in (2). All complexes exhibit an antiproliferative effect against B16 tumor cells and improved antibacterial and antifungal activities compared to the free ligands. Complex (3) displays the best antimicrobial activity against all four tested strains, both in the planktonic and biofilm-embedded states, which can be correlated to its stronger DNA-binding and nuclease-activity traits.

Microbial biofilms are represented by sessile microbial communities with modified gene expression and phenotype, adhered to a surface and embedded in a matrix of self-produced extracellular polymeric substances (EPS). Microbial biofilms can develop on both prosthetic devices and tissues, generating chronic and persistent infections that cannot be eradicated with classical organic-based antimicrobials, because of their increased tolerance to antimicrobials and the host immune system. Several complexes based mostly on 3D ions have shown promising potential for fighting biofilm-associated infections, due to their large spectrum antimicrobial and anti-biofilm activity. The literature usually reports species containing Mn(II), Ni(II), Co(II), Cu(II) or Zn(II) and a large variety of multidentate ligands with chelating properties such as antibiotics, Schiff bases, biguanides, N-based macrocyclic and fused rings derivatives. This review presents the progress in the development of such species and their anti-biofilm activity, as well as the contribution of biomaterials science to incorporate these complexes in composite platforms for reducing the negative impact of medical biofilms.

Two novel, pyridinone-based chelating ligands containing separated (O,O) and (Namino,Nhet) chelating sets (Namino = secondary amine; Nhet = pyrrole N for H(L3) (1-(3-(((1H-pyrrole-2-yl)methyl)-amino)propyl)-3-hydroxy-2-methylpyridin-4(1H)-one) or pyridine N for H(L5) (3-hydroxy-2-methyl-1-(3-((pyridin-2-ylmethyl)amino)propyl)pyridin-4(1H)-one)) were synthesized via reduction of the appropriate imines. Their proton dissociation processes were explored, and the molecular structures of two synthons were assessed by X-ray crystallography. These ambidentate chelating ligands are intended to develop Co(III)/PGM (PGM = platinum group metal) heterobimetallic multitargeted complexes with anticancer potential. To explore their metal ion binding ability, the interaction with Pd(II), [(η6-p-cym)Ru]2+ and [(η5-Cp*)Rh]2+ (p-cym = 1-methyl-4-isopropylbenzene, Cp* = pentamethyl-cyclopentadienyl anion) cations was studied in aqueous solution with the combined use of pH-potentiometry, NMR and HR ESI-MS. In general, organorhodium was found to form more labile complexes over ruthenium, while complexation of the (N,N) chelating set was slower than the processes of the pyridinone unit with (O,O) coordination. Formation of the organoruthenium complexes starts at lower pH (higher thermodynamic stabilities of the corresponding complexes) than for [(η5-Cp*)Rh]2+ but, due to the higher affinity of [η6-p-cym)Ru]2+ towards hydrolysis, the complexed ligands are capable of competing with hydroxide ion in a lesser extent than for the rhodium systems. As a result, under biologically relevant conditions, the rhodium binding effectivity of the ligands becomes comparable or even slightly higher than their effectivity towards ruthenium. Our results indicate that H(L3) is a less efficient (N,N) chelator for these metal ions than H(L5). Similarly, due to the relative effectivity of the (O,O) and (N,N) chelates at a 1:1 metal-ion-to-ligand ratio, H(L5) coordinates in a (N,N) manner to both cations in the whole pH range studied while, for H(L3), the complexation starts with (O,O) coordination. At a 2:1 metal-ion-to-ligand ratio, H(L3) cannot hinder the intensive hydrolysis of the second metal ion, although a small amount of 2:1 complex with [(η5-Cp*)Rh]2+ can also be detected.

In order to improve pharmaceutical properties of drugs, complexes are synthesized as combinations with other chemical substances. The complexes of fenamic acid and its derivatives, such as mefenamic-, tolfenamic- and flufenamic acid, with acridine were obtained and the X-ray structures were discussed. Formation of the crystals is determined by the presence of the intermolecular O–H…N hydrogen bond that occur between fenamic acids and acridine. Intermolecular interactions stabilizing the crystals such as π…π stacking, C–H…X (X = O, Cl) intermolecular hydrogen bonds as well as C–H…π and other dispersive interactions were analyzed by theoretical methods: the quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI) approaches.

Cardamonin is a polyphenolic natural product that has been shown to possess cytotoxic activity against a variety of cancer cell lines. We previously reported the semi-synthesis of a novel Cu (II)–cardamonin complex (19) that demonstrated potent antitumour activity. In this study, we further investigated the bioactivity of 19 against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective treatment for triple-negative breast cancer (TNBC) and pancreatic cancer, respectively. Results revealed that 19 abolished the formation of MDA-MB-468 and PANC-1 colonies, exerted growth-inhibitory activity, and inhibited cancer cell migration. Further mechanistic studies showed that 19 induced DNA damage resulting in gap 2 (G2)/mitosis (M) phase arrest and microtubule network disruption. Moreover, 19 generated reactive oxygen species (ROS) that may contribute to induction of apoptosis, corroborated by activation of caspase-3/7, PARP cleavage, and downregulation of Mcl-1. Complex 19 also decreased the expression levels of p-Akt and p-4EBP1, which indicates that the compound exerts its activity, at least in part, via inhibition of Akt signalling. Furthermore, 19 decreased the expression of c-Myc in PANC-1 cells only, which suggests that it may exert its bioactivity via multiple mechanisms of action. These results demonstrate the potential of 19 as a therapeutic agent for TNBC and pancreatic cancer.

Every year, more Cu(II) complexes are proven to be biologically active species, but very few are developed as drugs or entered in clinical trials. This is due to their poor water solubility and lipophilicity, low stability as well as in vivo inactivation. The possibility to improve their pharmacological and/or oral administration profile by incorporation into inorganic or organic matrix was studied. Most of them are either physically encapsulated or conjugated to the matrix via a moiety able to coordinate Cu(II). As a result, a large variety of species were developed as delivery carriers. The organic carriers include liposomes, synthetic or natural polymers or dendrimers, while the inorganic ones are based on carbon nanotubes, hydrotalcite and silica. Some hybrid organic-inorganic materials based on alginate-carbonate, gold-PEG and magnetic mesoporous silica-Schiff base were also developed for this purpose.

Four complexes, [Cu4L2(OCH3)2(CH3OH)2]·2H2O (1), [Zn2L2Cl4]·2H2O·2CH3OH (2), [Hg2L2Br4]·4CH3OH (3), and {[CdL2Cl2]·4H2O·4CH3OH}n (4), have been synthesized and characterized from a bis(pyridylhydrazone) ligand (L) with copper(II), zinc(II), mercury(II) or cadmium(II), respectively. Complex 1 exists as a centrosymmetric tetranuclear dimer with L as deprotonated tridentate ligand. Complexes 2 and 3 exist as centrosymmetric metallamacrocycles with L as bidentate ligand. Complex 4 exists as a 1D looped-chain coordination polymer. The thermal stabilities and vapor adsorption properties of the four complexes were investigated as well.

In order to synthesize new iron (II) complexes of 1,5-diaza-3,7-diphosphacyclooctanes with a wider variety of the substituents on ligands heteroatoms (including functionalized ones, namely, pyridyl groups) and co-ligands, it was found that these ligands with relatively small phenyl, benzyl, and pyridin-2-yl substituents on phosphorus atoms in acetonitrile formed bis-P,P-chelate cis-complexes [L2Fe(CH3CN)2]2+ (BF4)2−, whereas P-mesityl-substituted ligand formed only monoligand P,P-complex [LFe(CH3CN)4]2+ (BF4)2−. 3,7-dibenzyl-1,5-di(1′-(R)-phenylethyl)-1,5-diaza-3,7-diphosphacyclooctane reacted with hexahydrate of iron (II) tetrafluoroborate in acetone to give an unusual bis-ligand cationic complex of the composition [L2Fe(BF4)]+ BF4−, where two fluorine atoms of the tetrafluoroborate unit occupied two pseudo-equatorial positions at roughly octahedral iron ion, according to X-ray diffraction data. 1,5-diaza-3,7-diphosphacyclooctanes replaced tetrahydrofurane and one of the carbonyl ligands of cyclopentadienyldicarbonyl(tetrahydrofuran)iron (II) tetrafluoroborate to form heteroligand complexes [CpFeL(CO)]+BF4−. The structural studies in the solid phase and in solutions showed that diazadiphosphacyclooctane ligands of all complexes adopted chair-boat conformations so that their nitrogen atoms were in close proximity to the central iron ion. The redox properties of the obtained complexes were performed by the cyclic voltammetry method.

Two mononuclear zero-dimensional Ni(II) and Zn(II) complexes bearing diethylenetriamine derivative ligand, namely [NiL(CH3COO)2(H2O)] (1) and [ZnL(CH3COO)2] (2) [L = N, N’-bis(2-hydroxybenzyl)diethylenetriamine], were synthesized under reflux conditions. The molecular composition and structure of the complexes were identified by IR, PXRD, elemental analyses, and single crystal X-ray diffraction. Complex 1 belongs to a monoclinic crystal system with the P21/n space group, and Complex 2 belongs to a monoclinic crystal system with the C2/c space group. The Henry reaction of nitromethane with aromatic aldehydes was explored with Complexes 1 and 2 as the catalyst. Results from the catalytic reaction revealed that the complexes displayed excellent catalytic activities under the optimized conditions and that the substrate scope of aromatic aldehydes could be extended to a certain extent. In addition, the possible catalytic mechanism of the Henry reaction was also deduced.

Dietary intake of potato starch could induce a dramatic increase in blood glucose and is positively associated with chronic metabolic diseases (type II diabetes, cardiovascular disease, etc.). Grape seed proanthocyanidins (GSP) are known to decrease starch digestion by inhibiting digestive enzymes or changing the physicochemical properties of starch. In the present study, GSP were complexed with potato starch to prepare polyphenol−starch complexes. The physiochemical properties and digestibility of complexes were investigated by in vitro digestion model, X-ray diffraction, differential scanning calorimetry, rapid visco analyzer, Fourier transform infrared spectroscopy as well as texture profile analysis. Results indicated that the peak viscosity, breakdown, trough, and setback of the complexes disappeared, replaced by a special continuous increase in paste viscosity. The complexes showed a lower final viscosity and higher thermal stability with the increasing binding amount of GSP. GSP decreased the hardness of the complexes’ gel significantly. FT-IR indicated that GSP might interact with potato starch through noncovalent forces. Additionally, the complexes also showed a higher content of slowly digestible starch and resistant starch than that of the native starch. Thus, we inferred that the addition of GSP could modify the digestibility of potato starch and be an optional way to modify the starch with lower digestion.

Accumulation of α-synuclein (α-Syn) is a remarkable pathology for Parkinson’s disease (PD), therefore clearing it is possibly a promising strategy for treating PD. Aberrant copper (Cu(II)) homeostasis and oxidative stress play critical roles in the abnormal aggregation of α-Syn in the progress of PD. It is reported that the polyphenol (−)-epi-gallocatechin gallate (EGCG) can inhibit α-Syn fibrillation and aggregation, disaggregate α-Syn mature fibrils, as well as protect α-Syn overexpressed-PC12 cells against damage. Also, previous studies have reported that EGCG can chelate many divalent metal ions. What we investigate here is whether EGCG can interfere with the Cu(II) induced fibrillation of α-Syn and protect the cell viability. In this work, on a molecular and cellulaire basis, we demonstrated that EGCG can form a Cu(II)/EGCG complex, leading to the inhibition of Cu(II)-induced conformation transition of α-Syn from random coil to β-sheet, which is a dominant structure in α-Syn fibrils and aggregates. Moreover, we found that the mixture of Cu(II) and EGCG in a molar ratio from 0.5 to 2 can efficiently inhibit this process. Furthermore, we demonstrated that in the α-Syn transduced-PC12 cells, EGCG can inhibit the overexpression and fibrillation of α-Syn in the cells, and reduce Cu(II)-induced reactive oxygen species (ROS), protecting the cells against Cu(II)-mediated toxicity.

A multicyclophane with a core based on tris(2-aminoethyl)amine (TREN) linked by amide spacers to three fragments of pillar[5]arene was synthesized. The choice of the tris-amide core allowed the multicyclophane to bind to anion guests. The presence of three terminal pillar[5]arene units provides the possibility of effectively binding the colorimetric probe N-phenyl-3-(phenylimino)-3H-phenothiazin-7-amine (PhTz). It was established that the multicyclophane complexed PhTz in chloroform with a 1:1 stoichiometry (lgKa = 5.2 ± 0.1), absorbing at 650 nm. The proposed structure of the complex was confirmed by 1H-NMR spectroscopy: the amide group linking the pillar[5]arene to the TREN core forms a hydrogen bond with the PhTz imino-group while the pillararenes surround PhTz. It was established that the PhTz:tris-pillar[5]arene complex could be used as a colorimetric probe for fluoride, acetate, and dihydrogen phosphate anions due to the anion binding with proton donating amide groups which displaced the PhTz probe. Dye displacement resulted in a color change from blue to pink, lowering the absorption band at 650 nm and increasing that at 533 nm.

Quercetin is a bioactive compound that is widely used in botanical medicine and traditional Chinese medicine due to its potent antioxidant activity. In recent years, antioxidant activities of quercetin have been studied extensively, including its effects on glutathione (GSH), enzymatic activity, signal transduction pathways, and reactive oxygen species (ROS) caused by environmental and toxicological factors. Chemical studies on quercetin have mainly focused on the antioxidant activity of its metal ion complexes and complex ions. In this review, we highlight the recent advances in the antioxidant activities, chemical research, and medicinal application of quercetin.

Although they are widely used as insecticides, acaricides and fungicides in the agriculture or as raw materials in the dye industry, dinitrophenols (DNPs) are extremely noxious, death cases having been registered. These compounds produce cataracts, lower leucocyte levels, disturb the general metabolism and can cause cancer. It is also assumed that DNPs hinder the proton translocation through the mitochondrial inner membrane and therefore inhibit oxidative phosphorylation. Their fluorescence quenching properties can help understand and explain their toxicity. Fluorescence quenching of tryptophan was tested using different dinitrophenols such as 2,4-dinitrophenol (2,4-DNP), 4,6-dinitro-orthocresol (DNOC), 2-[(2,4-dinitrophenyl)amino]acetic acid (GlyDNP), 2-(1-methyl-heptyl)-4.6-dinitrophenyl crotonate (Karathan), 2-amino-5-[(1-((carboxymethyl)amino)-3-((2,4-dinitrophenyl)thio)-1-oxopropan-2-yl)amino]-5-oxopentanoic acid (SDN GSH), 2,4-dinitroanisole (2,4-DNA) and 2,4-dinitrobenzoic acid (2,4-DNB). 2,4-DNP and DNOC showed the highest tryptophan fluorescence quenching constant values, these being also the most toxic compounds. The electronic chemical potential value of the most stable complex of 2,4-DNP-with tryptophan is higher than the values of the electronic chemical potentials of complexes corresponding to the derivatives.

The effects of cyclodextrins and derivatives on the activity and structure of pullulanase were investigated in this study. Our results showed that cyclodextrins and derivatives decreased the activity of pullulanase. This decrease was attributed to the interaction between the hydrophobic cavities of cyclodextrins and pullulanase. The hydrophobic cavity was confirmed to encapsulate the groups of pullulanase molecules by the addition of competitive guests. The results obtained from fluorescence spectroscopy analysis showed that β-CD showed more efficient interactions with pullulanase molecules and the side chain groups of cyclodextrin significantly prevented the interaction between the hydrophobic cavities of β-CD and pullulanase molecules. These findings suggest that the geometric dimension of hydrophobic cavities was crucial for matching between cyclodextrins and pullulanase and steric hindrance caused by side chains led to the decrease of the interaction.

In this study a complex of naringenin with hydroxypropyl-β-cyclodextrin (HP-β-CD) was prepared to improve the hydrophilicity of naringenin. The physicochemical properties of the complex were analyzed by ultraviolet-visible spectrometry (UV), infrared spectrometry (IR), X-ray diffractometry (XRD), differential scanning calorimetry (DSC). The result showed that naringenin had been molecularly dispersed in the HP-β-CD matrix, not forming a new compound and HPLC analysis showed that the solubility of naringenin in water was enhanced from 4.38 μg/mL to 1,272.31 μg/mL.

A novel, mixed-valent copper(I)-copper(II) complex, {[bis(ethylene-diamine)copper(II)] bis[diiodocuprate(I)]} (1), has been prepared by electrochemicaldissolution of a sacrificial copper anode in a solution of ethylenediamine (en), I2 andtetraethylammoniumperchlorate (TEAP) as supporting electrolyte in acetonitrile (AcN)and characterized by single-crystal X-ray structure determination. The crystal structure ofthe complex 1 shows that it consists of a CuI2 polymer formed from I- ligands bridgingCu(I) ions, with a nearly square planar geometry of bivalente Cu(II) atoms chelated by twoethylenediamine ligands. The results also show that direct electrosynthesis of the complexhad high current efficiency, purity and electrolysis yield.

The mutual influence of ligands within the structure of Zn-porphyrins on the thermodynamic stability of the latter was investigated.

Although they are widely used as insecticides, acaricides and fungicides in the agriculture or as raw materials in the dye industry, dinitrophenols (DNPs) are extremely noxious, death cases having been registered. These compounds produce cataracts, lower leucocyte levels, disturb the general metabolism and can cause cancer. It is also assumed that DNPs hinder the proton translocation through the mitochondrial inner membrane and therefore inhibit oxidative phosphorylation. Their fluorescence quenching properties can help understand and explain their toxicity. Fluorescence quenching of tryptophan was tested using different dinitrophenols such as 2,4-dinitrophenol (2,4-DNP), 4,6-dinitroorthocresol (DNOC), 2-[(2,4-dinitrophenyl)amino]acetic acid (GlyDNP), 2-(1-methylheptyl)- 4.6-dinitrophenyl crotonate (Karathan), 2-amino-5-[(1-((carboxymethyl)amino)-3- ((2,4-dinitrophenyl)thio)-1-oxopropan-2-yl)amino]-5-oxopentanoic acid (SDN GSH), 2,4-dinitroanisole (2,4-DNA) and 2,4-dinitrobenzoic acid (2,4-DNB). 2,4-DNP and DNOC showed the highest tryptophan fluorescence quenching constant values, these being also the most toxic compounds. The electronic chemical potential value of the most stable complex of 2,4-DNP-with tryptophan is higher than the values of the electronic chemical potentials of complexes corresponding to the derivatives. [ABSTRACT FROM AUTHOR]

The effects of cyclodextrins and derivatives on the activity and structure of pullulanase were investigated in this study. Our results showed that cyclodextrins and derivatives decreased the activity of pullulanase. This decrease was attributed to the interaction between the hydrophobic cavities of cyclodextrins and pullulanase. The hydrophobic cavity was confirmed to encapsulate the groups of pullulanase molecules by the addition of competitive guests. The results obtained from fluorescence spectroscopy analysis showed that β-CD showed more efficient interactions with pullulanase molecules and the side chain groups of cyclodextrin significantly prevented the interaction between the hydrophobic cavities of β-CD and pullulanase molecules. These findings suggest that the geometric dimension of hydrophobic cavities was crucial for matching between cyclodextrins and pullulanase and steric hindrance caused by side chains led to the decrease of the interaction. [ABSTRACT FROM AUTHOR]

Microbial biofilms are represented by sessile microbial communities with modified gene expression and phenotype, adhered to a surface and embedded in a matrix of self-produced extracellular polymeric substances (EPS). Microbial biofilms can develop on both prosthetic devices and tissues, generating chronic and persistent infections that cannot be eradicated with classical organic-based antimicrobials, because of their increased tolerance to antimicrobials and the host immune system. Several complexes based mostly on 3D ions have shown promising potential for fighting biofilm-associated infections, due to their large spectrum antimicrobial and anti-biofilm activity. The literature usually reports species containing Mn(II), Ni(II), Co(II), Cu(II) or Zn(II) and a large variety of multidentate ligands with chelating properties such as antibiotics, Schiff bases, biguanides, N-based macrocyclic and fused rings derivatives. This review presents the progress in the development of such species and their anti-biofilm activity, as well as the contribution of biomaterials science to incorporate these complexes in composite platforms for reducing the negative impact of medical biofilms. [ABSTRACT FROM AUTHOR]

In an attempt to increase the biological activity of the 1,2,4-triazolo[1,5-a]pyrimidine scaffold through complexation with essential metal ions, the complexes trans-[Cu(mptp)2Cl2] (1), [Zn(mptp)Cl2(DMSO)] (2) (mptp: 5-methyl-7-phenyl-1,2,4-triazolo[1,5-a]pyrimidine), [Cu2(dmtp)4Cl4]·2H2O (3) and [Zn(dmtp)2Cl2] (4) (dmtp: 5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine), were synthesized and characterized as new antiproliferative and antimicrobial species. Both complexes (1) and (2) crystallize in the P21/n monoclinic space group, with the tetrahedral surroundings generating a square-planar stereochemistry in the Cu(II) complex and a tetrahedral stereochemistry in the Zn(II) species. The mononuclear units are interconnected in a supramolecular network through π–π interactions between the pyrimidine moiety and the phenyl ring in (1) while supramolecular chains resulting from C-H∙∙∙π interactions were observed in (2). All complexes exhibit an antiproliferative effect against B16 tumor cells and improved antibacterial and antifungal activities compared to the free ligands. Complex (3) displays the best antimicrobial activity against all four tested strains, both in the planktonic and biofilm-embedded states, which can be correlated to its stronger DNA-binding and nuclease-activity traits. [ABSTRACT FROM AUTHOR]

Around 5% of the population of the world is affected with the disease called diabetes mellitus. The main medication of the diabetes is the insulin; the active form is the insulin monomer, which is an instable molecule, because the long storage time, or the high temperature, can cause the monomer insulin to adapt an alternative fold, rich in β-sheets, which is pharmaceutically inactive. The aim of this study is to form different insulin complexes with all the cyclodextrin used for pharmaceutical excipients (native cyclodextrin, methyl, hydroxyethyl, hydroxypropyl and sulfobutylether substituted β-cyclodextrin), in silico condition, with the AutoDock molecular modeling program, to determine the best type of cyclodextrin or cyclodextrin derivate to form a complex with an insulin monomer, to predict the molar ratio, the conformation of the complex, and the intermolecular hydrogen bonds formed between the cyclodextrin and the insulin. From the results calculated by the AutoDock program it can be predicted that insulin can make a stable complex with 5–7 molecules of hydroxypropyl-β-cyclodextrin or sulfobutylether-β-cyclodextrin, and by forming a complex potentially can prevent or delay the amyloid fibrillation of the insulin and increase the stability of the molecule. [ABSTRACT FROM AUTHOR]

Cyclodextrin (CD) derivatives are a challenge, mainly due to solubility problems. In many cases, the synthesis of CD derivatives requires high-boiling solvents, whereas the product isolation from the aqueous methods often requires energy-intensive processes. Complex formation faces similar challenges in that it involves interacting materials with conflicting properties. However, many authors also refer to the formation of non-covalent bonds, such as the formation of inclusion complexes or metal–organic networks, as reactions or synthesis, which makes it difficult to classify the technical papers. In many cases, the solubility of both the starting material and the product in the same solvent differs significantly. The sweetest point of mechanochemistry is the reduced demand or complete elimination of solvents from the synthesis. The lack of solvents can make syntheses more economical and greener. The limited molecular movements in solid-state allow the preparation of CD derivatives, which are difficult to produce under solvent reaction conditions. A mechanochemical reaction generally has a higher reagent utilization rate. When the reaction yields a good guest co-product, solvent-free conditions can be slower than in solution conditions. Regioselective syntheses of per-6-amino and alkylthio-CD derivatives or insoluble cyclodextrin polymers and nanosponges are good examples of what a greener technology can offer through solvent-free reaction conditions. In the case of thiolated CD derivatives, the absence of solvents results in significant suppression of the thiol group oxidation, too. The insoluble polymer synthesis is also more efficient when using the same molar ratio of the reagents as the solution reaction. Solid reactants not only reduce the chance of hydrolysis of multifunctional reactants or side reactions, but the spatial proximity of macrocycles also reduces the length of the spacing formed by the crosslinker. The structure of insoluble polymers of the mechanochemical reactions generally is more compact, with fewer and shorter hydrophilic arms than the products of the solution reactions. [ABSTRACT FROM AUTHOR]

Two novel, pyridinone-based chelating ligands containing separated (O,O) and (Namino,Nhet) chelating sets (Namino = secondary amine; Nhet = pyrrole N for H(L3) (1-(3-(((1H-pyrrole-2-yl)methyl)-amino)propyl)-3-hydroxy-2-methylpyridin-4(1H)-one) or pyridine N for H(L5) (3-hydroxy-2-methyl-1-(3-((pyridin-2-ylmethyl)amino)propyl)pyridin-4(1H)-one)) were synthesized via reduction of the appropriate imines. Their proton dissociation processes were explored, and the molecular structures of two synthons were assessed by X-ray crystallography. These ambidentate chelating ligands are intended to develop Co(III)/PGM (PGM = platinum group metal) heterobimetallic multitargeted complexes with anticancer potential. To explore their metal ion binding ability, the interaction with Pd(II), [(η6-p-cym)Ru]2+ and [(η5-Cp*)Rh]2+ (p-cym = 1-methyl-4-isopropylbenzene, Cp* = pentamethyl-cyclopentadienyl anion) cations was studied in aqueous solution with the combined use of pH-potentiometry, NMR and HR ESI-MS. In general, organorhodium was found to form more labile complexes over ruthenium, while complexation of the (N,N) chelating set was slower than the processes of the pyridinone unit with (O,O) coordination. Formation of the organoruthenium complexes starts at lower pH (higher thermodynamic stabilities of the corresponding complexes) than for [(η5-Cp*)Rh]2+ but, due to the higher affinity of [η6-p-cym)Ru]2+ towards hydrolysis, the complexed ligands are capable of competing with hydroxide ion in a lesser extent than for the rhodium systems. As a result, under biologically relevant conditions, the rhodium binding effectivity of the ligands becomes comparable or even slightly higher than their effectivity towards ruthenium. Our results indicate that H(L3) is a less efficient (N,N) chelator for these metal ions than H(L5). Similarly, due to the relative effectivity of the (O,O) and (N,N) chelates at a 1:1 metal-ion-to-ligand ratio, H(L5) coordinates in a (N,N) manner to both cations in the whole pH range studied while, for H(L3), the complexation starts with (O,O) coordination. At a 2:1 metal-ion-to-ligand ratio, H(L3) cannot hinder the intensive hydrolysis of the second metal ion, although a small amount of 2:1 complex with [(η5-Cp*)Rh]2+ can also be detected. [ABSTRACT FROM AUTHOR]

In order to improve pharmaceutical properties of drugs, complexes are synthesized as combinations with other chemical substances. The complexes of fenamic acid and its derivatives, such as mefenamic-, tolfenamic- and flufenamic acid, with acridine were obtained and the X-ray structures were discussed. Formation of the crystals is determined by the presence of the intermolecular O–H...N hydrogen bond that occur between fenamic acids and acridine. Intermolecular interactions stabilizing the crystals such as π...π stacking, C–H...X (X = O, Cl) intermolecular hydrogen bonds as well as C–H...π and other dispersive interactions were analyzed by theoretical methods: the quantum theory of atoms in molecules (QTAIM) and noncovalent interaction (NCI) approaches. [ABSTRACT FROM AUTHOR]

Cardamonin is a polyphenolic natural product that has been shown to possess cytotoxic activity against a variety of cancer cell lines. We previously reported the semi-synthesis of a novel Cu (II)–cardamonin complex (19) that demonstrated potent antitumour activity. In this study, we further investigated the bioactivity of 19 against MDA-MB-468 and PANC-1 cancer cells in an attempt to discover an effective treatment for triple-negative breast cancer (TNBC) and pancreatic cancer, respectively. Results revealed that 19 abolished the formation of MDA-MB-468 and PANC-1 colonies, exerted growth-inhibitory activity, and inhibited cancer cell migration. Further mechanistic studies showed that 19 induced DNA damage resulting in gap 2 (G2)/mitosis (M) phase arrest and microtubule network disruption. Moreover, 19 generated reactive oxygen species (ROS) that may contribute to induction of apoptosis, corroborated by activation of caspase-3/7, PARP cleavage, and downregulation of Mcl-1. Complex 19 also decreased the expression levels of p-Akt and p-4EBP1, which indicates that the compound exerts its activity, at least in part, via inhibition of Akt signalling. Furthermore, 19 decreased the expression of c-Myc in PANC-1 cells only, which suggests that it may exert its bioactivity via multiple mechanisms of action. These results demonstrate the potential of 19 as a therapeutic agent for TNBC and pancreatic cancer. [ABSTRACT FROM AUTHOR]

Four complexes, [Cu4L2(OCH3)2(CH3OH)2]·2H2O (1), [Zn2L2Cl4]·2H2O·2CH3OH (2), [Hg2L2Br4]·4CH3OH (3), and {[CdL2Cl2]·4H2O·4CH3OH}n (4), have been synthesized and characterized from a bis(pyridylhydrazone) ligand (L) with copper(II), zinc(II), mercury(II) or cadmium(II), respectively. Complex 1 exists as a centrosymmetric tetranuclear dimer with L as deprotonated tridentate ligand. Complexes 2 and 3 exist as centrosymmetric metallamacrocycles with L as bidentate ligand. Complex 4 exists as a 1D looped-chain coordination polymer. The thermal stabilities and vapor adsorption properties of the four complexes were investigated as well. [ABSTRACT FROM AUTHOR]

Every year, more Cu(II) complexes are proven to be biologically active species, but very few are developed as drugs or entered in clinical trials. This is due to their poor water solubility and lipophilicity, low stability as well as in vivo inactivation. The possibility to improve their pharmacological and/or oral administration profile by incorporation into inorganic or organic matrix was studied. Most of them are either physically encapsulated or conjugated to the matrix via a moiety able to coordinate Cu(II). As a result, a large variety of species were developed as delivery carriers. The organic carriers include liposomes, synthetic or natural polymers or dendrimers, while the inorganic ones are based on carbon nanotubes, hydrotalcite and silica. Some hybrid organic-inorganic materials based on alginate-carbonate, gold-PEG and magnetic mesoporous silica-Schiff base were also developed for this purpose. [ABSTRACT FROM AUTHOR]