Aziz Kalilur Rahiman

Structural modeling, in vitro antiproliferative activity, and the effect of substituents on the DNA fastening and scission actions of heteroleptic copper(II) complexes with terpyridines and naproxen

A series of heteroleptic copper(II) complexes of the type [Cu(L1–6)(nap)Cl] (1–6) (L1–6 = 4′-(4-substituted)-2,2′:6′,2′′-terpyridines, nap = naproxen) has been synthesized and characterized. The single crystal analyses of complexes 1 and 6 show distorted octahedral geometry around the copper(II) ion. Structural parameters from the crystallographic and DFT studies are in good agreement with each other. HOMO–LUMO energy levels are constructed and the corresponding theoretical frontier energy gaps are calculated to understand the charge transfer occurring in the molecule, and the lowering of the HOMO–LUMO band gap supports the bioactive properties of the molecule. Electrochemical studies show a one-electron irreversible reduction process in the cathodic potential (Epc) region from −0.75 to −0.82 V. The obtained room-temperature magnetic moment values (1.82–1.93 BM), XRD and EPR spectral data support a distorted octahedral geometry for the copper(II) complexes. The binding studies of complexes 1, 5 and 6 with CT-DNA imply a groove mode of binding, and complex 5 exhibits a higher binding affinity than the other complexes. The binding results are further supported by molecular docking studies. The higher binding propensity of complex 5, containing R5, was proved by computationally derived factors such as chemical potential (μ), chemical hardness (η), electrophilicity (ω) and nuclease-independent chemical shift (NICS). All the complexes display pronounced nuclease activity against supercoiled pBR322 DNA. The in vitro antiproliferative activity of complexes 1, 5 and 6 against human breast cancer cells (MCF-7) was assessed by MTT assay, which shows the potency of 1 and 5, with lower IC50 values than cisplatin and values comparable to doxorubicin. The complexes induce mitochondrial-mediated and caspase-dependent apoptosis with an increase in G0–G1 and subsequent arrest in the S phase in cell cycle evaluation.

Magneto-structural correlation, antioxidant, DNA interaction and growth inhibition activities of new chloro-bridged phenolate complexes

A new class of chloro-bridged dinuclear nickel(II) and copper(II) phenolate complexes (1–8) were synthesized from 4-substituted-2-((2-(piperazin-1-yl)ethylimino)methyl)phenols (L1−4) and characterized. The XRD analysis of complexes 4 and 8 shows two mononuclear units connected through a bridged chlorine atom that gives dinuclear complexes. The stability of the complexes has been determined using a spectrophotometric method. Complexes 5–8 possess significant antioxidant activity against the DPPH radical. The binding studies of complexes with CT-DNA suggest partial intercalative/electrostatic interaction and the cleavage ability for pBR322 DNA shows the involvement of the hydroxyl radical as an intermediate in the cleavage reaction. The IC50 value of complexes 2, 6 and 8 against the HepG2 cell line is comparable with that of cisplatin. To find the extent of nuclear chromatin cleavage, propidium iodide staining and comet assays were employed. Among the newly synthesized complexes, copper(II) complexes exhibited superior biological activity when compared to their nickel(II) analogues.

New pyridazine-based binuclear nickel(II), copper(II) and zinc(II) complexes as prospective anticancer agents

A new class of pyridazine-based binuclear nickel(II), copper(II) and zinc(II) complexes of the type [M2(L1–3)2](NO3)2 (1–9) with tridentate Schiff base ligands 3-chloro-6-(salicylidenehydrazinyl)pyridazine (HL1), 3-chloro-6-(5-nitrosalicylidenehydrazinyl)pyridazine (HL2) and 3-chloro-6-(4-diethylaminosalicylidenehydrazinyl)pyridazine (HL3) was synthesized and characterized. The molecular structure of the ligand HL3 was determined by the single crystal XRD method. The geometry optimization and HOMO–LUMO energy level calculations were carried out using DFT studies. The electrochemical studies of nickel(II) (1–3) and copper(II) (4–6) complexes exhibit two irreversible one-electron reduction waves at 1Epc = −0.323 to −0.463 V and 2Epc = −0.634 to −0.790 V in the cathodic potential region. The nickel(II) complexes (1–3) exhibit two irreversible one-electron oxidation waves at 1Epa = 1.009 to 1.025 V and 2Epa = 1.140 to 1.153 V in the anodic potential region. The spectroscopic data indicate that the ligands behave as a monoanionic tridentate ligand through the deprotonated phenolic oxygen and nitrogen atoms of the azomethine group and the pyridazine ring. The emission studies of the complexes at room temperature indicate the enhancement of fluorescence intensity than the ligands due to the chelation-enhanced fluorescence effect (CHEF) suggesting them as possible fluorescent probes of these Schiff bases for metal ions. In vitro cytotoxic activity of all the complexes was assessed against one breast cancer (MDA-MB-231) cell line and one normal cell line (L-6 myoblast). The IC50 values of complexes 3 and 9 indicate their high cytotoxicity against MDA-MB-231 cells when compared to the standard drug cisplatin suggesting that these complexes may act as potential antitumor agents. Nuclear chromatin cleavage has also been observed with AO/EB staining assay. Flow cytometry analysis of complexes 3 and 9 revealed cell cycle arrest in the S phase. Molecular docking studies were also carried out for the complexes 3 and 9 to find their binding affinity with protein EGFR kinase.

Mixed-ligand binuclear copper(II) complex of 5-methylsalicylaldehyde and 2,2 -bipyridyl: Synthesis, crystal structure, DNA binding and nuclease activity

AbstractA new mixed-ligand binuclear copper(II) complex [Cu(MS)(bpy)]2.(ClO4)2, built of 5-methylsalicylaldehyde and 2,2′-bipyridyl has been synthesized and characterized by using elemental analysis, IR and UV-Vis spectroscopy. Crystal structure of the complex shows that copper(II) ion lies in a square pyramidal coordination environment. The structure consists of two symmetrical half units in which the copper(II) ion of one half unit connected with the phenolate oxygen atom of other half unit along with one perchlorate anion in the crystal lattice as free molecule. Presence of uncoordinated perchlorate anion was also confirmed by IR spectroscopy. Absorption spectroscopy exhibits d-d transition at 628 nm, which further supports the square pyramidal geometry around the copper(II) ions. EPR spectrum of the copper(II) complex at room temperature shows a broad signal without any splitting pattern at g|| = 2.26,g⊥ = 2.03 and the magnetic moment (μeff= 1.31 BM) obtained at room temperature indicate an antiferromagnetic interaction between the two copper(II) ions through phenoxide-bridge. Binding studies reveal that the complex possesses good binding propensity (Kb = 5.2 ± 1.7 × 104 M−1) and bind to nitrogenous bases of DNA through intercalation. Nuclease activity of the complex with pBR322 DNA shows that the effect of hydrolytic cleavage is dose-dependent and the oxidative cleavage indicates the involvement of hydroxyl radical and singlet-oxygen as reactive oxygen species. Graphical AbstractMixed-ligand binuclear copper(II) complex was isolated and characterized. The binding studies of the complex suggest the intercalation mode of binding with CTDNA. The nuclease activity with pBR322 DNA shows that the hydrolytic cleavage is dose-dependent and the oxidative mechanism implies the involvement of hydroxyl radical and singlet-oxygen as reactive oxygen species.

Hydroxy, carboxylic and amino acid functionalized superparamagnetic iron oxide nanoparticles: Synthesis, characterization and in vitro anti-cancer studies

AbstractSuperparamagnetic iron oxide nanoparticles were synthesized by simple co-precipitation method and modified with different coating agents such as ascorbic acid, hexanoic acid, salicylic acid, L-arginine and L-cysteine. The synthesized nanoparticles were characterized by various techniques such as FT IR, XRD, VSM, SEM, TEM and thermal analysis. Both bare and coated magnetites were of cubic spinel structure and spherical in shape. All the magnetite nanoparticles showed superparamagnetic behaviour with high saturated magnetization. In vitro cytotoxicity test of bare and coated nanoparticles was performed using adenocarcinoma cells, A549. Cell viability of bare and L-arginine coated magnetite nanoparticles showed IC50 value of 31.2 μg/mL proving the compatibility of nanocarriers when compared to others. Hence, L-arginine coated nanoparticles were used for loading the drug paclitaxel and the observed IC50 value (7.8 μg/mL) shows its potent anti-proliferative effect against A549 lung cancer cell lines. Thus, it can be speculated that the drug paclitaxel loaded L-arginine coated nanoparticles could be used as an effective drug carrier for the destruction of cancer cells. Graphical AbstractSuperparamagnetic magnetite nanoparticles coated with different acids were synthesized and characterized. The cytotoxicity of nanoparticles was observed using MTT assay on adenocarcinoma (A549) cancer cells. Paclitaxel drug loaded, L-arginine coated nanoparticles showed highest cytotoxicity. DNA fragmentation on A549 cell line resulted in the breakdown of DNA molecules proving anti-cancer activity of the nanoparticles.

In vitro and in vivo anti-proliferative evaluation of bis(4′-(4-tolyl)-2,2′:6′,2″-terpyridine)copper(II) complex against Ehrlich ascites carcinoma tumors

The bis(4′-(4-tolyl)-2,2′:6′,2″-terpyridine)copper(II) complex [Cu(ttpy)2]Cl2 was synthesized and authenticated by single crystal analysis, which shows distorted octahedral geometry around copper(II) ion. The crystal packing is stabilized by C–H···π inter and intramolecular interactions. The complex was found to be lipophilic as determined by shake-flask method. In vitro cytotoxicity of the complex was tested against Ehrlich ascites carcinoma (EAC) and L6 myotube cell lines. The complex exhibit potent cytotoxicity with respect to the commercially available anticancer drug cisplatin. Hoechst 33258, AO/EB and PI (flow cytometry) staining methods suggest that the complex can induce apoptosis in EAC cells. Cell cycle analyses also support the induced apoptosis. Cellular uptake studies revealed that the complex can go into the cytoplasm and accumulate in the cell nuclei. The complex induces EAC cell apoptosis through a ROS-mediated mitochondrial pathway by activating caspase 3 and caspase 7 and regulates the Bcl-2 family proteins. In vivo study of the complex was validated against the animal tumor growth (EAC) cell in Swiss albino mice.Graphical abstractThe bis(4′-(4-tolyl)-2,2′:6′,2″-terpyridine)copper(II) complex induces EAC cell apoptosis through a ROS-mediated mitochondrial pathway and significantly reduced the body weight and solid tumor volume in Swiss albino mice.

Copper complexes as prospective anticancer agents: in vitro and in vivo evaluation, selective targeting of cancer cells by DNA damage and S phase arrest

A series of six new bis(thiosemicarbazone)copper(I) complexes of the type [Cu(L1–6)2Cl] (1–6) have been synthesized and characterized. The molecular structure of the ligand L4 was determined by the single crystal XRD method. All the complexes adopted trigonal planar (Y-shaped) geometry. All the complexes strongly bind with CT-DNA via intercalative mode, which was further supported by molecular docking studies. Further, the complexes were effectively bind with BSA as observed by UV-Vis and fluorescence spectra. All the complexes effectively cleave pBR322 DNA through hydrolytic pathway as evidenced from T4 ligase experiments. All the complexes interact with the anticancer receptor focal adhesion kinase (FAK) via electrostatic, van der Waals, hydrogen bonding, σ–π and π–π interactions. In vitro cytotoxicity of the complexes were assessed by MTT assay against four cancer cell lines such as human breast adenocarcinoma (MCF-7), cervical (HeLa), epithelioma (Hep-2) and Ehrlich ascites carcinoma (EAC), and two normal cell lines namely normal human dermal fibroblasts (NHDF) and L6 myotubes with respect to the commercially used anticancer drug cisplatin. All the complexes induce apoptosis in EAC cells, which was confirmed by AO/EB, Hoechst 33258 and PI staining methods. The complexes block cell cycle progression of EAC cells in S phase (DNA synthesis). The cellular uptake studies confirmed the ability of the complexes to go into the cytoplasm and accumulation in the cell nuclei. In the in vivo anticancer studies, the complexes significantly reduce the tumour volume in female Swiss albino mice. Overall, our results ensure the role of thiosemicarbazone-based copper(I) complexes as prospective anticancer agents, induction of apoptosis and S phase arrest with the mitochondrial controlled pathway.