Search Results (38)

Anticancer drug design has been reformed by the creation of heterocyclic hybrids. The introduction of a quinoline scaffold affects the activity, toxicity, and bioavailability of new compounds. The aim of this study was to synthesize and evaluate the biological activity of hybrids of 1,4-naphthoquinone with the 8-hydroxyquinoline moiety. The structure of the new compounds was characterized using spectroscopic methods, such as HR-MS, NMR, and IR. The analysis was supplemented by calculated NMR and IR spectra. The physicochemical properties and bioavailability of the compounds were examined using in silico methods. An analysis of reactivity descriptors showed that the compounds are good electron acceptors and exhibit high reactivity. Bioavailability properties confirm that hybrids could be good oral administration drugs. The biological potential of hybrids was examined by designation of the enzymatic conversion rate of the NQO1 protein and in vitro against cancer cell lines with overexpression of the gene encoding the NQO1 protein. The possibility of interaction between the tested ligand and the NQO1 protein was examined by molecular docking methods. Full article

We report the synthesis and characterization of five novel metal complexes. Three of them are vanadium complexes with the general formula [VO(Lⁿ)₂], where Lⁿ are Schiff bases derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with either 4-(2-aminoethyl)morpholine (L¹), 3-morpholinopropylamine (L²) or 1-(2-aminoethyl)piperidine (L³). The two other metal complexes are [Ni(L¹)₂] and [Fe(L¹)₂]Cl. They were characterized by analytical, spectroscopic (Fourier transform infrared, UV-visible absorption), and mass spectrometric techniques as well as by single-crystal X-ray diffraction (for all [VO(Lⁿ)₂] complexes and [Ni(L¹)₂]). While, in the crystal structure, the V(IV)O complexes show distorted square–pyramidal geometry with the ligands bound as bidentate through quinolate NO donors, the Ni(II) complex shows octahedral geometry with two ligand molecules coordinated through NNO donors. Stability studies in aqueous media revealed that the vanadium complexes are not stable, undergoing oxidation to VO₂(L), which was corroborated by ⁵¹V NMR and MS. This behavior is also observed in organic media, though at a significantly slower rate. The Ni complex exhibited small spectral changes over time in aqueous media. Nonetheless, all compounds show enhanced stability in the presence of bovine serum albumin (BSA). Fluorescence studies carried out for the Ni(II) and Fe(III) complexes indicate reversible binding to albumin. The cytotoxicity of the L¹ metal complexes was assessed on melanoma (B16F10 and A375) and colon cancer (CT-26 and HCT-116) cell lines, with 5-fluorouracil (5-FU) as a reference drug. The V- and Ni complexes showed the lowest IC₅₀ values (<10 μM) in either A375 or HCT-116 cells after 48 h of incubation, while the Fe(III) complex presented minimal antiproliferative effects. The complexes were generally more cytotoxic to human than murine cancer cells. Synergistic in vitro studies with 5-FU revealed antagonism in most cases, except in A375 cells, where an additive effect was observed for the combination with the V-complex. Overall, these compounds show promising potential for cancer treatment, mostly for melanoma. Full article

Zinc is integral to diverse biological functions, acting catalytically, structurally, and supportively in essential enzyme cycles, despite its limited amounts in the body. Targeting zinc enzymes with potent drugs, such as Vorinostat, demonstrates the therapeutic efficacy of zinc-binding ligands, notably in cutaneous T-cell lymphoma treatments. Our study merges experimental and theoretical approaches to analyze the coordination of 8-hydroxylquinoline (8HQ) inhibitors with biomimetic zinc complexes and human histone deacetylase 8 (HDAC8), a monozinc hydrolase enzyme. Assessing 10 8HQ derivatives for structural and electronic characteristics against these models, we observe minimal inhibition efficacy, corroborated through protein–ligand docking analyses, highlighting the complexities of inhibitor–zinc enzyme interactions and suggesting intricate noncovalent interactions that are important for ligand binding to enzymes not accounted for in model zinc hydrolase mimics. Full article

A heterocyclic compound of S and N with cyclic structures, like Furans, thiophenes and related azole analogs, is important as a ligand because of it is readily available, stable and easily functionalized. Various types of heterocyclic molecules quinazolines and their derivatives contain important chromophores with desirable electrochemical properties to be applied in the sensor field. Metal complexes of these compounds have demonstrated significant electrochemical properties as ionophore or electroactive materials for the fabrication of ISEs with different polymeric membranes. R. Selva Kumar et al. 2019 reported the use of dibutyl(8-hydroxyquinolin-2-yl)methylphosphonate as ionophore in a PVC matrix for the fabrication of a potentiometric thorium(IV) ion-selective electrode These quinazoline-based membranes with other additives and plasticizers are very useful for the development of a potential difference across the membrane at membrane-solution interface in the required proportions . Analytes, such as Butralin, Hydroxylamine, and Nitrite, and heavy metal ions, like Fe³⁺ and Th⁴⁺, have also been determined using quinazoline-based membrane sensors. ISE-based electrochemical sensors are very useful in the analysis of food products, drinking water, beverages, fertilizers, soil industrial effluents, etc. They also are applied in potentiometric titration as indicator electrodes. Full article

The isoelectronic relationship of 1,2-azaborinine (B=N structural motif) and benzene (C=C) is well documented. Upon deprotonation of the former, the anionic 1,2-azaboratabenzene is obtained, which is isosteric with pyridine (C=N) and has a similar capability as an aromatic N-donor. We present the complexation of boron and aluminum precursors with a κ²-N,O-donating 8-hydroxy-BN-naphthalene ligand (H₂(BQ), 1). Six chelate complexes with 1:1 and 2:1 stoichiometries were isolated and characterized by X-ray diffraction analysis and NMR spectroscopy. Comparing the isosteric dimethylaluminum complexes of H₂(BQ) and an 8-hydroxyquinoline (HQ’, 2) as a reference allowed us to quantify the influence of a formal substitution of carbon by boron on the structure and the electronic properties: While the structural parameters of the ligands were similar, the electropositive boron atom affected the electron density distributions within the complexes substantially. As the consequence, the Al–N bond was significantly shortened, and the aluminum atom showed a different coordination geometry than in the quinoline analog. Moreover, strong hypsochromic shifts of both the absorption and the emission were observed. The results highlight that the differences between CN and BN polyaromatic complexes are more distinct than between equally charged BN and CC congeners. Full article

The metal chelator PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) acts as a terdentate ligand capable of forming binary and ternary Cu²⁺ complexes. It was clinically trialed as an Alzheimer’s disease (AD) therapy but failed to progress beyond phase II. The β-amyloid (Aβ) peptide associated with AD was recently concluded to form a unique Cu(Aβ) complex that is inaccessible to PBT2. Herein, it is shown that the species ascribed to this binary Cu(Aβ) complex in fact corresponds to ternary Cu(PBT2)N_Im^Aβ complexes formed by the anchoring of Cu(PBT2) on imine nitrogen (N_Im) donors of His side chains. The primary site of ternary complex formation is His6, with a conditional stepwise formation constant at pH 7.4 ($K_c^{}$ [M⁻¹]) of log$K_{}^c$ = 6.4 ± 0.1, and a second site is supplied by His13 or His14 (log$K_{}^c$ = 4.4 ± 0.1). The stability of Cu(PBT2)N_Im^H13/14 is comparable with that of the simplest Cu(PBT2)N_Im complexes involving the N_Im coordination of free imidazole (log$K_{}^c$ = 4.22 ± 0.09) and histamine (log$K_{}^c$ = 4.00 ± 0.05). The 100-fold larger formation constant for Cu(PBT2)N_Im^H6 indicates that outer-sphere ligand–peptide interactions strongly stabilize its structure. Despite the relatively high stability of Cu(PBT2)N_Im^H6, PBT2 is a promiscuous chelator capable of forming a ternary Cu(PBT2)N_Im complex with any ligand containing an N_Im donor. These ligands include histamine, L-His, and ubiquitous His side chains of peptides and proteins in the extracellular milieu, whose combined effect should outweigh that of a single Cu(PBT2)N_Im^H6 complex regardless of its stability. We therefore conclude that PBT2 is capable of accessing Cu(Aβ) complexes with high stability but low specificity. The results have implications for future AD therapeutic strategies and understanding the role of PBT2 in the bulk transport of transition metal ions. Given the repurposing of PBT2 as a drug for breaking antibiotic resistance, ternary Cu(PBT2)N_Im and analogous Zn(PBT2)N_Im complexes may be relevant to its antimicrobial properties. Full article

Histamine receptor 2 (HR_H2) blockers are used to treat peptic ulcers and gastric reflux. Chlorquinaldol and chloroxine, which contain an 8-hydroxyquinoline (8HQ) core, have recently been identified as blocking HR_H2. To gain insight into the mode of action of 8HQ-based blockers, here, we leverage an HR_H2-based sensor in yeast to evaluate the role of key residues in the HR_H2 active site on histamine and 8HQ-based blocker binding. We find that the HR_H2 mutations D98A, F254A, Y182A, and Y250A render the receptor inactive in the presence of histamine, while HR_H2:D186A and HR_H2:T190A retain residual activity. Based on molecular docking studies, this outcome correlates with the ability of the pharmacologically relevant histamine tautomers to interact with D98 via the charged amine. Docking studies also suggest that, unlike established HR_H2 blockers that interact with both ends of the HR_H2 binding site, 8HQ-based blockers interact with only one end, either the end framed by D98/Y250 or T190/D186. Experimentally, we find that chlorquinaldol and chloroxine still inactivate HR_H2:D186A by shifting their engagement from D98 to Y250 in the case of chlorquinaldol and D186 to Y182 in the case of chloroxine. Importantly, the tyrosine interactions are supported by the intramolecular hydrogen bonding of the 8HQ-based blockers. The insight gained in this work will aid in the development of improved HR_H2 therapeutics. More generally, this work demonstrates that Gprotein-coupled receptor (GPCR)-based sensors in yeast can help elucidate the mode of action of novel ligands for GPCRs, a family of receptors that bind 30% of FDA therapeutics. Full article

Two tetranuclear [Zn₄Cl₂(ClQ)₆]·2DMF (1) and [Zn₄Cl₂(ClQ)₆(H₂O)₂]·4DMF (2), as well as three dinuclear [Zn₂(ClQ)₃(HClQ)₃]I₃ (3), [Zn₂(dClQ)₂(H₂O)₆(SO₄)] (4) and [Zn₂(dBrQ)₂(H₂O)₆(SO₄)] (5), complexes (HClQ = 5-chloro-8-hydroxyquinoline, HdClQ = 5,7-dichloro-8-hydroxyquinoline and HdBrQ = 5,7-dibromo-8-hydroxyquinoline) were prepared as possible anticancer or antimicrobial agents and characterized by IR spectroscopy, elemental analysis and single crystal X-ray structure analysis. The stability of the complexes in solution was verified by NMR spectroscopy. Antiproliferative activity and selectivity of the prepared complexes were studied using in vitro MTT assay against the HeLa, A549, MCF-7, MDA-MB-231, HCT116 and Caco-2 cancer cell lines and on the Cos-7 non-cancerous cell line. The most sensitive to the tested complexes was Caco-2 cell line. Among the tested complexes, complex 3 showed the highest cytotoxicity against all cell lines. Unfortunately, all complexes showed only poor selectivity to normal cells, except for complex 5, which showed a certain level of selectivity. Antibacterial potential was observed for complex 5 only. Moreover, the DNA/BSA binding potential of complexes 1–3 was investigated by UV-vis and fluorescence spectroscopic methods. Full article

Multidrug resistance (MDR) in cancer is one of the major obstacles of chemotherapy. We have recently identified a series of 8-hydroxyquinoline Mannich base derivatives with MDR-selective toxicity, however with limited solubility. In this work, a novel 5-nitro-8-hydroxyquinoline-proline hybrid and its Rh(η⁵-C₅Me₅) and Ru(η⁶-p-cymene) complexes with excellent aqueous solubility were developed, characterized, and tested against sensitive and MDR cells. Complex formation of the ligand with essential metal ions was also investigated using UV-visible, circular dichroism, ¹H NMR (Zn(II)), and electron paramagnetic resonance (Cu(II)) spectroscopic methods. Formation of mono and bis complexes was found in all cases with versatile coordination modes, while tris complexes were also formed with Fe(II) and Fe(III) ions, revealing the metal binding affinity of the ligand at pH 7.4: Cu(II) > Zn(II) > Fe(II) > Fe(III). The ligand and its Rh(III) complex displayed enhanced cytotoxicity against the resistant MES-SA/Dx5 and Colo320 human cancer cell lines compared to their chemosensitive counterparts. Both organometallic complexes possess high stability in solution, however the Ru(II) complex has lower chloride ion affinity and slower ligand exchange processes, along with the readiness to lose the arene ring that is likely connected to its inactivity. Full article

Six new copper(II) complexes were prepared: [Cu(ClBrQ)₂] (1a, 1b), [Cu(ClBrQ)₂]·1/2 diox (2) (diox = 1,4-dioxane), [Cu(BrQ)₂] (3), [Cu(dNQ)₂] (4), [Cu(dNQ)₂(DMF)₂] (5) and [Cu(ClNQ)₂] (6), where HClBrQ is 5-chloro-7-bromo-8-hydroxyquinoline, HBrQ is 7-bromo-8-hydroxyquinoline, HClNQ is 5-chloro-7-nitro-8-hydroxyquinoline and HdNQ is 5,7-dinitro-8-hydroxyquinoline. Prepared compounds were characterised by infrared spectroscopy, elemental analysis and by X-ray structural analysis. Structural analysis revealed that all complexes are molecular. Square planar coordination of copper atoms in [Cu(XQ)₂] (XQ = ClBrQ (1a, 1b), BrQ (3) and ClNQ (6)) and tetragonal bipyramidal coordination in [Cu(dNQ)₂(DMF)₂] (5) complexes were observed. In these four complexes, bidentate chelate coordination of XQ ligands via oxygen and nitrogen atoms was found. Hydrogen bonds stabilizing the structure were observed in [Cu(dNQ)₂(DMF)₂] (5) and [Cu(ClNQ)₂] (6), no other nonbonding interactions were noticed in all five structures. The stability of the complexes in DMSO and DMSO/water was evaluated by UV-Vis spectroscopy. Cytotoxic activity of the complexes and ligands was tested against MCF-7, MDA-MB-231, HCT116, CaCo2, HeLa, A549 and Jurkat cancer cell lines. The selectivity of the complexes was verified on a noncancerous Cos-7 cell line. Antiproliferative activity of the prepared complexes was very low in comparison with cisplatin, except complex 3; however, its activity was not selective and was similar to the activity of its ligand HBrQ. Antibacterial potential was observed only with ligand HClNQ. Radical scavenging experiments revealed relatively high antioxidant activity of complex 3 against ABTS radical. Full article

Designing new metallodrugs for anticancer therapy is a driving force in the scientific community. Aiming to contribute to this field, we hereby report the development of a Schiff base (H₂L) derived from the condensation of 2-carbaldehyde-8-hydroxyquinoline with 2-hydrazinobenzothiazole and its complexation with transition metal ions. All compounds were characterised by analytical and spectroscopic techniques, which disclosed their structure: [Cu(HL)Cl], [Cu(HL)₂], [Ni(HL)(acetate)], [Ni(HL)₂], [Ru(HL)Cl(DMSO)], [VO(HL)₂] and [Fe(HL)₂Cl(H₂O)]. Different binding modes were proposed, showing the ligand’s coordination versatility. The ligand proton dissociation constants were determined, and the tested compounds showed high lipophilicity and light sensitivity. The stability of all complexes in aqueous media and their ability to bind to albumin were screened. Based on an antiproliferative in vitro screening, [Ni(HL)(acetate)] and [Ru(HL)Cl(DMSO)] were selected for further studies aiming to investigate their mechanisms of action and therapeutic potential towards colon cancer. The complexes displayed IC₅₀ < 21 μM towards murine (CT-26) and human (HCT-116) colon cancer cell lines. Importantly, both complexes exhibited superior antiproliferative properties compared to the clinically approved 5-fluorouracil. [Ni(HL)(acetate)] induced cell cycle arrest in S phase in CT-26 cells. For [Ru(HL)Cl(DMSO)] this effect was observed in both colon cancer cell lines. Additionally, both compounds significantly inhibited cell migration particularly in the human colon cancer cell line, HCT-116. Overall, the therapeutic potential of both metal complexes was demonstrated. Full article

Synthesis of thiazolidinone based on quinolone moiety was established starting from 4-hydroxyquinol-2-ones. The strategy started with the reaction of ethyl bromoacetate with 4-hydroxyquinoline to give the corresponding ethyl oxoquinolinyl acetates, which reacted with hydrazine hydrate to afford the hydrazide derivatives. Subsequently, hydrazides reacted with isothiocyanate derivatives to give the corresponding N,N-disubstituted thioureas. Finally, on subjecting the N,N-disubstituted thioureas with dialkyl acetylenedicarboxylates, cyclization occurred, and thiazolidinone derivatives were obtained in good yields. The two series based on quinolone moiety, one containing N,N-disubstituted thioureas and the other containing thiazolidinone functionalities, were screened for their in vitro urease inhibition properties using thiourea and acetohydroxamic acid as standard inhibitors. The inhibition values of the synthesized thioureas and thiazolidinones exhibited moderate to good inhibitory effects. The structure−activity relationship revealed that N-methyl quinolonyl moiety exhibited a superior effect, since it was proved to be the most potent inhibitor in the present series achieving (IC₅₀ = 1.83 ± 0.79 µM). The previous compound exhibited relatively much greater activity, being approximately 12-fold more potent than thiourea and acetohydroxamic acid as references. Molecular docking analysis showed a good protein−ligand interaction profile against the urease target (PDBID: 4UBP), emphasizing the electronic and geometric effect of N,N-disubstituted thiourea. Full article

The first examples of metallasilsesquioxane complexes, including ligands of the 8-hydroxyquinoline family 1–9, were synthesized, and their structures were established by single crystal X-ray diffraction using synchrotron radiation. Compounds 1–9 tend to form a type of sandwich-like cage of Cu₄M₂ nuclearity (M = Li, Na, K). Each complex includes two cisoid pentameric silsesquioxane ligands and two 8-hydroxyquinoline ligands. The latter coordinates the copper ions and corresponding alkaline metal ions (via the deprotonated oxygen site). A characteristic (size) of the alkaline metal ion and a variation of characteristics of nitrogen ligands (8-hydroxyquinoline vs. 5-chloro-8-hydroxyquinoline vs. 5,7-dibromo-8-hydroxyquinoline vs. 5,7-diiodo-8-hydroxyquinoline) are highly influential for the formation of the supramolecular structure of the complexes 3a, 5, and 7–9. The Cu₆Na₂-based compound 2 exhibits high catalytic activity towards the oxidation of (i) hydrocarbons by H₂O₂ activated with HNO₃, and (ii) alcohols by tert-butyl hydroperoxide. Studies of kinetics and their selectivity has led us to conclude that it is the hydroxyl radicals that play a crucial role in this process. Full article

A new series of tin(II) complexes (1, 2, 4, and 5) were successfully synthesized by employing hydroxy functionalized pyridine ligands, specifically 2-hydroxypyridine (hpH), 8-hydroxyquinoline (hqH), and 10-hydroxybenzo[h]quinoline (hbqH) as stabilizing ligands. Complexes [Sn(μ-κ²ON-OC₅H₄N)(N{SiMe₃}₂)]₂ (1) and [Sn₄(μ-κ²ON-OC₅H₄N)₆(κ¹O-OC₅H₄N)₂] (2) are the first structurally characterized examples of tin(II) oxypyridinato complexes exhibiting {Sn₂(OCN)₂} heterocyclic cores. As part of our study, ¹H DOSY NMR experiments were undertaken using an external calibration curve (ECC) approach, with temperature-independent normalized diffusion coefficients, to determine the nature of oligomerisation of 2 in solution. An experimentally determined diffusion coefficient (298 K) of 6.87 × 10⁻¹⁰ m² s⁻¹ corresponds to a hydrodynamic radius of Ca. 4.95 Å. This is consistent with the observation of an averaged hydrodynamic radii and equilibria between dimeric [Sn{hp}₂]₂ and tetrameric [Sn{hp}₂]₄ species at 298 K. Testing this hypothesis, ¹H DOSY NMR experiments were undertaken at regular intervals between 298 K–348 K and show a clear change in the calculated hydrodynamic radii form 4.95 Å (298 K) to 4.35 Å (348 K) consistent with a tetramer ⇄ dimer equilibria which lies towards the dimeric species at higher temperatures. Using these data, thermodynamic parameters for the equilibrium (ΔH° = 70.4 (±9.22) kJ mol⁻¹, ΔS° = 259 (±29.5) J K⁻¹ mol⁻¹ and ΔG°₂₉₈ = −6.97 (±12.7) kJ mol⁻¹) were calculated. In the course of our studies, the Sn(II) oxo cluster, [Sn₆(m³-O)₆(OR)₄:{Sn^(II)(OR)₂}₂] (3) (R = C₅H₄N) was serendipitously isolated, and its molecular structure was determined by single-crystal X-ray diffraction analysis. However, attempts to characterise the complex by multinuclear NMR spectroscopy were thwarted by solubility issues, and attempts to synthesise 3 on a larger scale were unsuccessful. In contrast to the oligomeric structures observed for 1 and 2, single-crystal X-ray diffraction studies unambiguously establish the monomeric 4-coordinate solid-state structures of [Sn(κ²ON-OC₉H₆N)₂)] (4) and [Sn(κ²ON-OC₁₃H₈N)₂)] (5). Full article

Achieving multi-color luminescence with a single atomic center in transition metal complexes is a challenge. In this work, luminescent materials with tunable emission properties were realized by complexation between aluminum (III) ions with the ligands 3-hydroxyflavone (3-HF) and 5,7-dichloro-8-hydroxyquinoline (DCHQ). Aluminum (III) complexes with a single ligand emitted blue from 3-HF and green from DCHQ. High quantum yields (QYs) of 29.42% and 37.00% were also obtained, respectively. DFT calculations revealed details of the photophysical properties of the complexes. Correspondingly, cyan light emission was obtained if these two complexes were mixed together, from which the emission wavelength was located at 470 nm and the QY was 20.52%, under 290 nm excitation. More importantly, the cyan light emitted by the mixtures had selective sensitivity to different metal ions, resulting in either quenching the fluorescence (in the case of Fe³⁺) or enhancing the fluorescence (in the case of In³⁺). The fluorescence enhancement effect of In³⁺ on metal complexes has not been previously reported, neither for transition metal nor lanthanide ions. The linear quenching behavior of Fe³⁺ functions in the 50–700 μM concentration range, and the linear enhancement behavior of In³⁺ is demonstrated in the 300–800 mM concentration range. Full article