Synthesis, Characterization, DNA/HSA Interactions, and Anticancer Activity of Two Novel Copper(II) Complexes with 4-Chloro-3-Nitrobenzoic Acid Ligand.
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ABSTRACT:
SUBMITTER: Zeng ZF
PROVIDER: S-EPMC8271622 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Three copper(ii) complexes, [Cu(L1)(NO3)2] (C1), [Cu(L2)Cl2] (C2) and [Cu(L2)SO4]2·H2O (C3), were designed and synthesized by the reaction of Cu(NO3)2·3H2O, CuCl2·2H2O and CuSO4·5H2O with a quinoline-derived Schiff base ligand, L1 or L2, prepared by the condensation of quinoline-8-carbaldehyde with 4-aminobenzoic acid methyl ester or 4-aminobenzoic acid ethyl ester (benzocaine). The efficient bindings of the C1-C3 complexes with human serum albumin (HSA) and calf thymus DNA (CT-DNA) were analyzed by spectroscopy and molecular docking. These complexes could significantly quench the fluorescence of HSA through the static quenching process, and hydrophobic interactions with HSA through the sub-domain IIA and IIIA cavities. The complexes bind to DNA via the intercalative mode and they fit well into the curved contour of the DNA target in the minor groove region. Furthermore, the interaction abilities of the Cu(ii) complexes with HSA/DNA were greater as compared to their corresponding ligands. Interestingly, C1-C3, particularly C3, exhibited more cytotoxicity toward HeLa cells compared to normal HL-7702 cells and three other tumor cell lines (Hep-G2, NCI-H460, and MGC80-3). Their cytotoxicity toward the HeLa cell lines was 1.9-3.5-fold more potent than cisplatin. Further studies indicated that these complexes arrested the cell cycle in the G0/G1 phase and promoted tumor cell apoptosis via a reactive oxygen species (ROS)-mediated mitochondrial pathway.
| S-EPMC6194498 | biostudies-literature
Project description:α-N-Heterocyclic thiosemicarbazones such as triapine and COTI-2 are currently investigated as anticancer therapeutics in clinical trials. However, triapine was widely inactive against solid tumor types. A likely explanation is the short plasma half-life time and fast metabolism. One promising approach to overcome these drawbacks is the encapsulation of the drug into nanoparticles (passive drug-targeting). In a previous work we showed that it was not possible to stably encapsulate free triapine into liposomes. Hence, in this manuscript we present the successful preparation of liposomal formulations of the copper(II) complexes of triapine and COTI-2. To this end, various drug-loading strategies were examined and the resulting liposomes were physico-chemically characterized. Especially for liposomal Cu-triapine, a decent encapsulation efficacy and a slow drug release behavior could be observed. In contrast, for COTI-2 and its copper(II) complex no stable loading could be achieved. Subsequent in vitro studies in different cell lines with liposomal Cu-triapine showed the expected strongly reduced cytotoxicity and DNA damage induction. Also in vivo distinctly higher copper plasma levels and a continuous release could be observed for the liposomal formulation compared to free Cu-triapine. Taken together, the here presented nanoformulation of Cu-triapine is an important step further to increase the plasma half-life time and tumor targeting properties of anticancer thiosemicarbazones.
| S-EPMC8594434 | biostudies-literature
Project description:Herein, we have synthesized and characterized a new benzimidazole-derived "BnI" ligand and its copper(II) complex, [Cu(BnI)?], 1, and zinc(II) complex, [Zn(BnI)?], 2, using elemental analysis and various spectroscopic techniques. Interaction of complexes 1 and 2 with the biomolecules viz. HSA (human serum albumin) and DNA were studied using absorption titration, fluorescence techniques, and in silico molecular docking studies. The results exhibited the significant binding propensity of both complexes 1 and 2, but complex 1 showed more avid binding to HSA and DNA. Also, the nuclease activity of 1 and 2 was analyzed for pBR322 DNA, and the results obtained confirmed the potential of the complexes to cleave DNA. Moreover, the mechanistic pathway was studied in the presence of various radical scavengers, which revealed that ROS (reactive oxygen species) are responsible for the nuclease activity in complex 1, whereas in complex 2, the possibility of hydrolytic cleavage also exists. Furthermore, the cytotoxicity of the ligand and complexes 1 and 2 were studied on a panel of five different human cancer cells, namely: HepG2, SK-MEL-1, HT018, HeLa, and MDA-MB 231, and compared with the standard drug, cisplatin. The results are quite promising against MDA-MB 231 (breast cancer cell line of 1), with an IC50 value that is nearly the same as the standard drug. Apoptosis was induced by complex 1 on MDA-MB 231 cells predominantly as studied by flow cytometry (FACS). The adhesion and migration of cancer cells were also examined upon treatment of complexes 1 and 2. Furthermore, the in vivo chronic toxicity profile of complexes 1 and 2 was also studied on all of the major organs of the mice, and found them to be less toxic. Thus, the results warrant further investigations of complex 1.
| S-EPMC5983663 | biostudies-literature
Project description:A mononuclear Cu(II) complex [Cu(HL)(o-phen)]·H2O (1) [H3L =, o-phen = 1,10-phenanthroline] was isolated from methanol, and its X-ray single-crystal structure was determined. Frozen glass X-band EPR of 1 in dimethylformamide (DMF) at LNT showed a spectrum that is characteristic of a monomeric tetragonal character with g ∥ = 2.164, g ⊥ = 2.087, A ∥ = 19.08 mT, and A ⊥ ≤ 4 mT. Electronic spectroscopic studies using calf thymus DNA (CT-DNA) showed strong binding affinity of 1 as reflected from its intrinsic binding constant (K b) value of 2.85 × 105 M-1. Competitive behavior of 1 with ethidium bromide (EB) displayed intercalative binding of DNA (K app = 1.3 × 106 M-1). The compound displayed significant oxidative cleavage of pUC19 DNA. The interaction between HSA and complex 1 was examined by employing fluorescence and electronic absorption spectroscopic experiments. The secondary and tertiary structures of HSA were found to be altered as suggested by three-dimensional (3D) fluorescence experiments. The affinity of 1 to bind to HSA was found to be strong as indicated from its value of the binding constant (K a = 2.89 × 105 M-1). Intrinsic fluorescence of the protein was found to be reduced through a mechanism of static quenching as suggested from the k q (2.01 × 1013 M-1 s-1) value, the bimolecular quenching constant. The Förster resonance energy transfer (FRET) process may also be accounted for such a high k q value. The r value (2.85 nm) calculated from FRET theory suggested that the distance between complex 1 (acceptor) and HSA (donor) is quite close. Complex 1 primarily bound to HSA in subdomain IIA as suggested by molecular docking studies. IC50 values (0.80 and 0.43 μM, respectively) obtained from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with HeLa and MCF7 cells suggested remarkable in vitro anticancer activity of 1. Nuclear dual staining assays revealed that cell death occurred via apoptosis in HeLa cells and reactive oxygen species (ROS) accumulation caused apoptosis induction. On treatment with a 5 μM dose of 1 in HeLa cells, the cell population significantly increased in the G2/M phase, while it was decreased in G0/G1 and S phases as compared to the control, clearly indicating G2/M phase arrest.
| S-EPMC8792924 | biostudies-literature
Project description:Transition metal coordination complexes have provided cancer treatment with new insights to overcome the limitations of current chemotherapeutic agents. Utilization of bifunctional tetrazole-carboxylate ligands with Zn(ii) obtained two self-assembled complexes [Zn(HL1)(bipy)3/2(H2O)]·CH3OH·4(H2O) (1) (H3L1 = 1,3,5-tri(2-carboxymethyltetrazol-5-yl) benzene) and [Zn(L2)2(H2O)2]2·2H2O (2) (HL2 = (5-pyridin-3-yl-tetrazol-2-yl)-acetic acid). The X-ray diffraction results showed that the two complexes displayed a two-dimensional (2D) layer structure and a one-dimensional (1D) layer structure. Nanocoprecipitation with DSPE-PEG-2000 resulted in the formation of complex nanoparticles (NPS) with excellent water dispersion. In vitro CCK-8 assay indicated the two NPs exert high cytotoxicity and sensitivity and a low half-maximum inhibitory concentration (IC50) towards HeLa than HepG2 cells. In addition, the cytotoxicity was also confirmed by live/dead co-stained experiments. The presented experimental results showed the 1 and 2 NPs were capable of inhibiting cell proliferation in vitro and may help design coordination complex-based anticancer candidates for cancer cells.
| S-EPMC9693915 | biostudies-literature
Project description:The isolated copper(II) complex [CuL(o-phen)]·H2O (1) [H2L = o-HO-C6H4C(H)=N-C6H4-SH-o, o-phen = 1,10-phenanthroline] was structurally characterized using single-crystal X-ray crystallography. 1 in CH3CN at liquid nitrogen temperature displayed a characteristic monomeric X-band electron paramagnetic resonance spectrum having a tetragonal character with g ∥ = 2.1479 and g ⊥ = 2.0691 and A ∥ ≈ 18.0 mT and A ⊥ ≤ 3.9 mT, respectively. 1 showed a strong binding affinity toward calf thymus DNA as reflected from its intrinsic binding constant (K b = 7.88 × 105 M-1), and its competitive displacement of ethidium bromide suggested an intercalative DNA-binding mode (K app = 1.32 × 106 M-1). This was confirmed from the viscosity study that showed an increase in the viscosity of DNA with an increasing concentration of 1. Complex 1 is highly efficient in promoting oxidative and hydrolytic DNA cleavage (k obs = 1.987 h-1). 1 showed a strong binding affinity with the carrier protein human serum albumin (HSA) (K a = 5.22 × 105 M-1). A high bimolecular quenching constant k q = 2.29 × 1013 M-1s-1 indicated a static quenching mechanism involved in the fluorescence quenching of HSA by 1. Fluorescence resonance energy transfer theory suggested that the distance (r = 3.52 nm) between 1 and HSA is very close. Molecular docking studies suggested that 1 primarily binds to HSA in subdomain IIA. A protein-ligand interaction profiler was used to visualize hydrophobic, hydrogen bonds, and π-cation interactions between HSA and 1. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using HeLa and MDA-MB-231 cells showed a significant in vitro anticancer activity of 1 (IC50 2.63 and 2.68 μM, respectively). Nuclear staining assays suggested apoptotic cell death in HeLa cells treated with 1. The effect of 1 on the cytoskeletal actin filaments visualized using phalloidin staining showed extensive destruction of actin filaments. Flow cytometric analysis indicated that 1 inhibits the growth of HeLa cells through cell cycle arrest in the S phase. Western blot analysis showed upregulation in the expression of apoptotic marker proteins caspase 3, p53, and Bax. These results collectively indicate that 1 induces apoptosis by promoting DNA damage and has a high potential to act as an anticancer agent.
| S-EPMC9245097 | biostudies-literature
Project description:We report the synthesis and characterization of a group of benzoylhydrazones (Ln) derived from 2-carbaldehyde-8-hydroxyquinoline and benzylhydrazides containing distinct para substituents (R = H, Cl, F, CH3, OCH3, OH and NH2, for L1-7, respectively; in L8 isonicotinohydrazide was used instead of benzylhydrazide). Cu(II) complexes were prepared by reaction of each benzoylhydrazone with Cu(II) acetate. All compounds were characterized by elemental analysis and mass spectrometry as well as by FTIR, UV-visible absorption, NMR or electron paramagnetic resonance spectroscopies. Complexes isolated in the solid state (1-8) are either formulated as [Cu(HL)acetate] (with L1 and L4) or as [Cu(Ln)]3 (n = 2, 3, 5, 6, 7 and 8). Single crystal X-ray diffraction studies were done for L5 and [Cu(L5)]3, confirming the trinuclear formulation of several complexes. Proton dissociation constants, lipophilicity and solubility were determined for all free ligands by UV-Vis spectrophotometry in 30% (v/v) DMSO/H2O. Formation constants were determined for [Cu(LH)], [Cu(L)] and [Cu(LH-1)] for L = L1, L5 and L6, and also [Cu(LH-2)] for L = L6, and binding modes are proposed, [Cu(L)] predominating at physiological pH. The redox properties of complexes formed with L1, L5 and L6 are investigated by cyclic voltammetry; the formal redox potentials fall in the range of +377 to +395 mV vs. NHE. The binding of the Cu(II)-complexes to bovine serum albumin was evaluated by fluorescence spectroscopy, showing moderate-to-strong interaction and suggesting formation of a ground state complex. The interaction of L1, L3, L5 and L7, and of the corresponding complexes with calf thymus DNA was evaluated by thermal denaturation. The antiproliferative activity of all compounds was evaluated in malignant melanoma (A-375) and lung (A-549) cancer cells. The complexes show higher activity than the corresponding free ligand, and most complexes are more active than cisplatin. Compounds 1, 3, 5, and 8 were selected for additional studies: while these complexes induce reactive oxygen species and double-strand breaks in both cancer cells, their ability to induce cell-death by apoptosis varies. Within the set of compounds tested, 8 emerges as the most promising one, presenting low IC50 values, and high induction of oxidative stress and DNA damage, which eventually lead to high rates of apoptosis.
| S-EPMC10072326 | biostudies-literature
Project description:Antimicrobial drug resistance poses a significant threat worldwide, hence triggering an urgent situation for developing feasible drugs. 3D-transition metal coordination complexes being multifaceted, offer tremendous potency as drug candidates. However, there are fewer reports on non-toxic and safe transition metal complexes; therefore, we hereby attempted to develop novel copper and vanadium-based therapeutic agents. We have synthesised six metal complexes viz., [VVO2(Quibal-INH)] (1), [CuII(Quibal-INH)2] (2), [VVO(Quibal-INH) (cat)] (3), [CuII(Quibal-INH) (cat)] (4), [VVO(Quibal-INH) (bha)] (5) and [CuII(Quibal-INH) (bha)] (6). Quibal-INH (L) is an ON bidentate donor ligand synthesized from Schiff base reaction between 4-(2-(7-chloroquinolin-3-yl)vinyl)benzaldehyde (Quibal) and Isoniazid (INH). The synthesized compounds were characterized using analytical techniques involving ATR-IR, UV-Vis, EPR, 1H NMR, 13C NMR, and 51V NMR. Ligand (L) and compound 3 exhibited moderate growth inhibitory activity towards Candida albicans and Cryptococcus neoformans fungal species. Compound 6 has been identified as active against the above fungal species with no toxicity and hemolysis activity on the healthy cells. Compound 5 exhibited significant activity against the Mycobacterium tuberculosis H 37 R v strain. Further, compounds 4, 5 and 6 exhibited excellent free radical scavenging activity. All the developed compounds were found to exhibit stability over a wide range of pH conditions. The complexes were additionally studied for their interaction with human serum albumin (HSA) with the UV-vis spectroscopic technique.
| S-EPMC9403362 | biostudies-literature
Project description:Copper(II) carboxylate complexes [Cu2(OOCR)4L2] (1) and [Cu2(OOCR`)4OCO(R`)CuL2]n (2), where L = 2-methyl pyridine, R = 2-chlorophenyl acetate and R` = 2-fluorophenyl acetate were synthesized and characterized by FT-IR spectroscopy and single crystal X-ray analysis. Complex 1 exhibits the typical paddlewheel array of a dinuclear copper(II) complex with carboxylate ligands. In complex 2, this scaffold is further extended into a polymeric arrangement based on alternate paddlewheel and square planar moieties with distinct coordination spheres. The complexes showed better 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radical scavenging activities and have been found to be more potent antileishmanial agents than their corresponding free ligand acid species. UV-Vis absorption titrations revealed good DNA binding abilities {Kb = 9.8 × 104 M-1 (1) and 9.9 × 104 M-1 (2)} implying partial intercalation of the complexes into DNA base pairs along with groove binding. The complexes displayed in vitro cytotoxic activity against malignant glioma U-87 (MG U87) cell lines. Computational docking studies further support complex-DNA binding by intercalation. Molecular docking investigations revealed probable interactions of the complexes with spike protein, the nucleocapsid protein of SARS-CoV-2 and with the angiotensin converting enzyme of human cells.
| S-EPMC8716173 | biostudies-literature
Project description:Copper(II) complexes with the first-generation quinolone antibacterial agent norfloxacin containing a nitrogen donor heterocyclic ligand 2,2'-bipyridine (bipy) or 1,10-phenanthroline (phen) were prepared and characterized by IR, EPR spectra, molar conductivity, and elemental analyses. The experimental data suggest that norfloxacin was coordinated to copper(II) through the carboxylato and ketone oxygen atoms. The interaction of the copper(II) complexes with bovine serum albumin (BSA) and human serum albumin (HSA) was investigated using fluorescence quenching of the tryptophan residues and copper(II) EPR spectroscopy. The results of fluorescence titration revealed that copper(II) complexes have a moderate ability to quench the intrinsic fluorescence of the albumins through a static quenching mechanism. EPR experiments showed that BSA and HSA Cu(II) sites compete with NOR for Cu(II)-bipy and Cu(II)-phen to form protein mixed-ligand complexes. Copper(II) complexes, together with the corresponding ligands, were evaluated for their trypanocidal activity in vitro against Trypanosoma cruzi, the causative agent of Chagas disease. The tests performed using bloodstream trypomastigotes showed that the Cu(II)-N-donor precursors and the metal complexes were more active than the free fluoroquinolone.
| S-EPMC4746275 | biostudies-literature