Spectroscopic and theoretical approach of DNA interaction and anticancer studies of bio-pharmaceutically active pyrimidine derived Cu(II) and Zn(II) complexes.

New metal(II) complexes (CuL2 and ZnL2) with pyrimidine appended Schiff base ligand (HL) were synthesized and characterized by diverse spectroscopic methods, reveals the proposed structure of metal(II) complexes possess square planar geometry. DNA interaction ability of isolated compounds was studied by UV-Visible, fluorescence, viscometric and electrochemical methods and the results showed that isolated compounds intercalated with calf thymus DNA (CT-DNA). In addition, anticancer activities of HL, CuL2, and ZnL2 have been evaluated by MTT assay, signifying moderate cytotoxic activity on selected cancer cell lines and less toxicity on NHDF normal cell line due to the specific targeting of pyrimidine analogues. Moreover, antioxidant activities of isolated compounds towards diverse free radicals have been studied by spectrophotometric methods. These results showed that CuL2 has better antioxidant ability than HL and ZnL2. Finally, antimicrobial activities of isolated compounds against selected antimicrobial pathogens exposed that CuL2 has better antimicrobial activity on E. coli and C. albicans than other antimicrobial pathogens. The DFT calculations have been done to get the optimized geometry of the ligand and the metal complexes. In order to get a broad understanding of the interactions of these synthesized metal complexes, a detailed molecular docking analysis is taken up.

ROS-Responsive Chitosan Coated Magnetic Iron Oxide Nanoparticles as Potential Vehicles for Targeted Drug Delivery in Cancer Therapy.

BACKGROUND AND OBJECTIVE: Cancer cells accumulate high concentrations of reactive oxygen species as a result of their faster and uninhibited metabolic activity. Cancer chemotherapeutic agents release an excess of severe adverse reactions as a result of targeting normal cells. This demands an improvement in targeted drug-delivery systems to selectively discharge anticancer drugs in the vicinity of such highly metabolically and mitotically active cells. MATERIALS AND METHODS: Here, magnetic nanoparticles were synthesized by a traditional co-precipitation technique. Fe3O4@OA-CS-5-FLU-NPs were synthesized by an easy and rapid in situ loading method. The proposed Fe3O4@OA-CS-5-FLU-NPs were productively prepared as well as characterized by various spectroscopic and microscopic studies. RESULTS: The targeted drug release profile of the Fe3O4@OA-CS-5-FLU-NPs was studied in the presence of ROS including H2O2 and pH induction. The released product, Fe3O4@OA-CS-5-FLU-NP, exhibited desirable levels of cytotoxicity and demonstrated morphological changes and inhibition of colony formation for A549 and HeLa S3 cancer cells. The IC50 values at 24 hours were 12.9 and 23 µg/mL, respectively. CONCLUSION: In summary, results from the MTT assay, fluorescence staining as well as colony formation assays, revealed that the Fe3O4@OA-CS-5-FLU-NPs were active and safe for anticancer biomedical applications. In summary, the present investigation provides a powerful nanostructured based system for improved cancer theranostics that should be further studied.

Bidentate Schiff Base Ligands Appended Metal(II) Complexes as Probes of DNA and Plasma Protein: In Silico Molecular Modelling Studies.

HL1 and HL2 (HL1 = 5-diethylamino-2-({[4-(diethylamino)phenyl]imino}methyl)-phenol; HL2 = 5-diethylamino-2-({[4-(dimethylamino)phenyl]imino}methyl)-phenol) are new Schiff base ligands which were prepared along with their metal(II) complexes of [Cu(L1)2] (1), [Cu(L1)2] (2), [Ni(L2)2] (3) and [Ni(L2)2] (4) and characterized by different analytical as well as spectroscopic analyses. The single crystal XRD analysis confirms the proposed structure of ligands such as HL1 and HL2. EPR spectral analysis gives evidence about the tetrahedrally coordinated geometry of complexes 1 and 2. Density functional theory (DFT) analysis was executed using B3LYP/6-31G(d,p)∪LanL2DZ level. The DNA sequence (along with Dickerson's sequence) specificity of complexes 1-4 was evaluated and it has resulted that the complexes 1-4 primarily interact with double helix of DNA via groove mode of binding. From plasma protein docking results, we can say that complexes 2 and 4 showed more binding towards HSA and may have good bioavailability and are prone to act as drug candidates. The observed findings show that these metal(II) complexes 1-4 are better DNA probes, will act as anticancer agents and stimulate strong research focusing on the design of new chemical probes of DNA.

Biological Impacts of Metal(II) Complex-Based DNA Probes Derived from Bidentate N,O Donor Schiff Base Ligand.

In this article, we have reported the preparation and structural characterization of a new Schiff base ligand (E)-2-(((2,6-difluorophenyl)imino)methyl)phenol (HSBL) and its derived metal(II) complexes [Cu(SBL)2] (1), [Ni(SBL)2] (2) and [Pd(SBL)2] (3). Using various analytical and spectroscopic techniques, their structural properties have been appraised. The proposed chemical structure of HSBL has been confirmed by Single crystal XRD studies. Bidentate characteristic of HSBL and its coordination with metal(II) ions through the oxygen atom of the phenolic group and nitrogen atom of the azomethine group have been evaluated from the FT-IR spectral analysis. Pd(II) complex of HSBL (complex 3) has found to be efficient in bringing about the interaction with DNA as well as BSA molecules. The in vitro antimicrobial studies have been demonstrated that complex 3 has a superior antimicrobial activity than HSBL, complexes 1 and 2. According to the values of zone of inhibition, the antimicrobial ability has been increased in the order of 3 > 1 > 2 > HSBL. A significant decrease in percent cell viability has been suggested that complex 3 has remarkable cytotoxicity (IC50 = 15.7 ± 0.6 µg/mL) on human breast cancer (MCF-7) cells. Besides, their induced apoptosis pathway of cytotoxicity has been demonstrated by fluorescence staining techniques using AO/EB staining method. We hope this article will be very helpful for future research on the development of new anticancer agents.

Iron oxide nanoparticle core-shell magnetic microspheres: Applications toward targeted drug delivery.

This study describes a sensitive reactive oxygen species (ROS)-responsive lecithin (LEC) incorporated iron oxide nanoparticle (Fe3O4 NP) system with potent anti-inflammatory properties and even more so when the antioxidant drug curcumin (CUR) is encapsulated in the PLGA hybrid magnetic microsphere system (Fe3O4@LEC-CUR-PLGA-MMS). The delivery system is responsive to ROS including an H2O2 environment to release the payload (CUR) drug. Greater cytotoxicity properties were observed in the presence of Fe3O4@LEC-CUR-PLGA-MMS against A549 and HeLa S3 cells with IC50 values after 24 h of 10 and 12 µg/mL and 10 and 20 µg/mL, respectively. The present Fe3O4@LEC-CUR-PLGA-MMS system demonstrated much better in vitro cytotoxicity, cellular morphological changes and moreover an ability to limit colony formation for A549 and HeLa S3 cancer cell lines than non-cancerous cells, and thus, should be further studied for a wide range of medical applications.

New bio-sensitive and biologically active single crystal of pyrimidine scaffold ligand and its gold and platinum complexes: DFT, antimicrobial, antioxidant, DNA interaction, molecular docking with DNA/BSA and anticancer studies.

Novel gold and platinum complexes [AuL2]·Cl, 1 and [PtL2]·2Cl, 2 with ligand, 2-methoxy-6-((2-(4-(trifluoromethyl)pyrimidin-2-yl)hydrazono)methyl)phenol (HL) have been synthesized and screened for their antimicrobial, antioxidant, DNA binding and anticancer (in vitro) activities. The single crystal of ligand HL was obtained by slow evaporation technique. The molecular structure of HL was confirmed from single crystal X-ray technique. Density functional theory calculations have been performed to gain insights into the electronic structure of these metal complexes. Antimicrobial result shows that, HL and complexes (1 and 2) have good antimicrobial agents against E. coli (bacteria) and C. albicans (fungi) than others bacterial and fungal strains. Antioxidant assay results suggest that, HL and complexes (1 and 2) possess good radical scavenging activity against diverse free radicals (DPPH, SOD, NO and H2O2). The intercalative interactions of HL and complexes (1 and 2) with CT-DNA were confirmed from spectroscopic titrations and viscometric measurements. Furthermore, the interactions of prepared compounds with DNA were confirmed by molecular docking analysis. In order to understand the nature of interactions between these metal complexes and BSA protein results clearly shows that complex 1 binds better than that of complex 2. The antitumor activities of prepared products were tested against single normal and different tumor cell lines by MTT assay. These results reveal that prepared complexes (1 and 2) have significant cytotoxic effect against tumor cell lines.

Spectroscopic, Computational, Antimicrobial, DNA Interaction, In Vitro Anticancer and Molecular Docking Properties of Biochemically Active Cu(II) and Zn(II) Complexes of Pyrimidine-Ligand.

Biochemically active Cu(II) and Zn(II) complexes [CuL(ClO4)2(1) and ZnL(ClO4)2(2)] have been synthesized from N,N donor Schiff base ligand L derived from4,6-dichloropyrimdine-5-carboxaldehyde with 4-(2-aminoethyl)morpholine. The L, complexes 1 and 2 have been structurally characterized by elemental analysis, 1H-NMR, FTIR, MS, UV-Visible and ESR techniques. The results obtained from the spectral studies supports the complexes 1 and 2 are coordinated with L through square planar geometry. DFT calculations results supports, the ligand to metal charge transfer mechanism can occur between L and metal(II) ions. The antimicrobial efficacy results have been recommended that, complexes 1 and 2 are good anti-pathogenic agents than ligand L. The interaction of complexes 1 and 2 with calf thymus (CT) DNA has been studied by electronic absorption, viscometric, fluorometric and cyclic voltammetric measurements. The calculated Kb values for L, complexes 1 and 2 found from absorption titrations was 4.45 × 104, L; 1.92 × 105, 1 and 1.65 × 105, 2. The Ksv values were found to be 3.0 × 103, 3.68 × 103and 3.52 × 103 for L, complexes 1 and 2 by using competitive binding with ethidium bromide (EB). These results suggest that, the compounds are interacted with DNA may be electrostatic binding. The molecular docking studies have been carried out to confirm the interaction of compounds with DNA. Consequently, in vitro anticancer activities of L, complexes 1 and 2 against selected cancer (lung cancer A549, liver cancer HepG2 and cervical carcinoma HeLa) and normal (NHDF) cell lines were assessed by MTT assay.

Crystal structure, optical properties, DFT analysis of new morpholine based Schiff base ligands and their copper(II) complexes: DNA, protein docking analyses, antibacterial study and anticancer evaluation.

New morpholine derived Schiff base ligands (HL1 and HL2) and their Cu(II) complexes [Cu(L1)2] (1) and [Cu(L2)2] (2) have been synthesized and characterized by 1H NMR, IR, UV-Vis, EPR studies and cyclic voltammetric analyses. Single crystal X-ray crystallography studies confirm the structure of newly synthesized Schiff base ligands HL1and HL2. The ground state electronic structures of Cu(II) complexes 1 and 2 have been investigated by DFT/B3LYP theoretical analysis with 6-31G (d,p) and LANL2DZ basis set. The affinity towards DNA and protein molecules have been evaluated using computational docking analysis and complex 2 expose significant binding ability with DNA as well as protein due to its towering hydrophobicity. Consequently, complex 2 reveals superior antibacterial activity against some bacterial species besides anticancer activity on human breast cancer (MCF-7) cells than complex 1 and Schiff base ligands (HL1 and HL2). These preliminary investigations strongly recommended that complex 2 can be used as a better antibacterial plus anticancer agent.

Multispectroscopic and bioimaging approach for the interaction of rhodamine 6G capped gold nanoparticles with bovine serum albumin.

Binding interaction of Bovine Serum Albumin (BSA) with newly prepared rhodamine 6G-capped gold nanoparticles (Rh6G-Au NPs) under physiological conditions (pH 7.2) was investigated by a wide range of photophysical techniques. Rh6G-Au NPs caused the static quenching of the intrinsic fluorescence of BSA that resulted from the formation of ground-state complex between BSA and Rh6G-Au NPs. The binding constant from fluorescence quenching method (Ka = 1.04 × 104 L mol-1; LoD = 14.0 µM) is in accordance with apparent association constant (Kapp = 1.14 × 101 M-1), which is obtained from absorption spectral studies. Förster resonance energy transfer (FRET) efficiency between the tryptophan (Trp) residue of BSA and fluorophore of Rh6G-Au NPs during the interaction was calculated to be 90%. The free energy change (ΔG = -23.07 kJ/mol) of BSA-Rh6G-Au NPs complex was calculated based on modified Stern-Volmer Plot. The time-resolved fluorescence analysis confirmed that quenching of BSA follows static mechanism through the formation of ground state complex. Furthermore, synchronous and three-dimensional fluorescence measurement, Raman spectral analysis and Circular Dichroism spectrum results corroborate the strong binding between Rh6G-Au NPs and BSA, which causes the conformational changes on BSA molecule. In addition, fluorescence imaging experiments of BSA in living human breast cancer (HeLa) cells was successfully demonstrated, which articulated the value of Rh6G-Au NPs practical applications in biological systems.

A theranostic nanocomposite system based on iron oxide-drug nanocages for targeted magnetic field responsive chemotherapy.

In this work, a theranostic nanocage system was developed for the targeted delivery of the anti-cancer agents camptothecin (CPT) and luotonin A (LuA). The core of the nanocage system (Fe3O4@OA-AD-SP NCs) was formed by biogenically synthesized Fe3O4 nanoparticles (NPs) decorated with a model anti-cancer drug (AD) and biosurfactant saponin (SP). The Fe3O4@OA-AD-SP NCs showed a high lipophilic AD loading efficiency (>80%) and a controlled pH-responsive drug release in stimulated cancerous cells in pH 6.4 media buffer. In addition, Fe3O4@OA-AD-SP NCs exhibited better serum protein binding efficacy at physiological pH values (7.4), furthering the important role of SP surface decoration. Particularly, these NCs showed better chemotherapeutic efficacy when examined in MCF-7 and HeLa cancer cell lines with a specific targeting capacity. Therefore, this study provides a new nano platform based on magnetic targeting and pH responsive lipophilic anticancer drug delivery to the cancer site.

Magnetic iron oxide nanoparticles (MIONs) cross-linked natural polymer-based hybrid gel beads: Controlled nano anti-TB drug delivery application.

The nanosized rifampicin (RIF) has been prepared to increase the solubility in aqueous solution, which leads to remarkable enhancement of its bioavailability and their convenient delivery system studied by newly produced nontoxic, biodegradable magnetic iron oxide nanoparticles (MIONs) cross-linked polyethylene glycol hybrid chitosan (mCS-PEG) gel beads. The functionalization of both nano RIF and mCS-PEG gel beads were studied using various spectroscopic and microscopic techniques. The size of prepared nano RIF was found to be 70.20 ± 3.50 nm. The mechanical stability and swelling ratio of the magnetic gel beads increased by the addition of PEG with a maximum swelling ratio of 38.67 ± 0.29 g/g. Interestingly, this magnetic gel bead has dual responsive assets in the nano drug delivery application (pH and the magnetic field). As we expected, magnetic gel beads show higher nano drug releasing efficacy at acidic medium (pH = 5.0) with maximum efficiency of 71.00 ± 0.87%. This efficacy may also be tuned by altering the external magnetic field and the weight percentage (wt%) of PEG. These results suggest that such a dual responsive magnetic gel beads can be used as a potential system in the nano drug delivery applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1039-1050, 2018.

One pot synthesis of new poly(vinyl alcohol) blended natural polymer based magnetic hydrogel beads: Controlled natural anticancer alkaloid delivery system.

Facile one-pot synthesis has been demonstrated for new biocompatible and dual responsive magnetic iron oxide nanoparticles cross-linked poly(vinyl alcohol) (PVA) blended natural polymer chitosan (CS) based hydrogel beads (mCS-PVA) as a controlled natural anticancer alkaloid Luotonin A (LuA) delivery system. The prepared magnetic hydrogel beads were characterized using powder X-ray diffraction measurement, Fourier transform-infrared spectroscopy, scanning electron microscopy, energy dispersive X-ray spectroscopy, and vibrating sample magnetometer. The magnetic hydrogel beads are exhibited significant water retention and follow the second order kinetic model in swelling study. The swelling ratio of the magnetic gel beads increased by the addition of PVA and showed a maximum swelling ratio of 40.83 ± 1.01 g/g and follows non-Fickian water transport mechanism. Stimuli responsive mCS and mCS-PVA hydrogel beads functionalized with LuA is demonstrated for controlled release at physiological pH and under magnetic field. The magnetic hydrogel beads show highest LuA releasing efficacy at acidic medium (pH = 5.0) with maximum efficiency of 73.33 ± 1.44%. This efficacy may also be tuned by altering the external magnetic field as well as the weight percentage (wt %) of polyethylene glycol. It is clearly that the newly produced magnetic hydrogel beads can be served as an effective intestinal LuA delivery system. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 543-551, 2018.

Biologically Active Cu(II), Co(II), Ni(II) and Zn(II) Complexes of Pyrimidine Derivative Schiff Base: DNA Binding, Antioxidant, Antibacterial and In Vitro Anticancer Studies.

A new pyrimidine derivative Schiff base ligand (HL) [HL = 2-(4,6-dimethylpyrimidin-2-ylimino)methyl)-4-nitrophenol] and its metal(II) complexes [CuL2] (1), [CoL2] (2), [NiL2] (3) and [ZnL2] (4) have been synthesized and characterized by several spectral techniques. The square planar geometry of the complexes 1-4 confirmed by UV-Visible, ESR and EI-mass spectral techniques. DNA binding study of the complexes 1-4 with Calf Thymus (CT) DNA using absorption spectral titration at different pH (4.0, 7.0 & 10.0) have been scrutinized that the complexes 1-4 bound by groove binding mode with significant binding constant values (K b  = 5.61 × 105 M-1 (1), 2.60 × 105 M-1 (2), 2.48 × 105 M-1 (3) and 6.98 × 104 M-1 (4) at pH = 10.0. Binding nature of the complexes 1-4 with CT DNA has further confirmed by emission, viscometry and cyclic voltammetry which also recommended that complexes 1-4 bound with CT DNA. The complexes 1-4 possessed effective scavenging effect during the DPPH and SOD radical scavenging method. The antibacterial activity of the complexes 1-4 was vetted against several bacterial strains and the results shows that the ligand (HL) and complexes 1-4 are more active in Bascillus subtilis. The anticancer activity of the complexes 1-4 was evaluated against Human Breast Cancer Cells (MCF-7), Human Cervical Cancer Cells (HeLa), Human Laryngeal Epithelial Carcinoma (HEp2) and Normal Human Dermal Fibroblast (NHDF) by MTT assay, which revealed that complexes 1 & 2 have modest activity against the cancer cell lines than ligand (HL) and complexes 3 & 4.

Study of non-covalent interactions of luotonin A derivatives and the DNA minor groove as a first step in the study of their analytical potential as DNA probes.

The interaction between DNA and several newly synthesized derivatives of the natural anticancer compound luotonin A has been studied. The results from our work reveal an effective and selective alkaloid/double-stranded DNA (ds-DNA) interaction. In the presence of increasing amounts of ds-DNA, a noticeable fluorescence quenching of the luotonin A derivatives under study was observed. However, this effect did not take place when single-stranded DNA (ss-DNA) was employed. The association constant alkaloids/ds-DNA was calculated by quantitation of such a quenching effect. The influence of other quenchers, namely Co(2+) and Br(-) on the native fluorescence of luotonin A and derivatives was also studied, and a remarkable quenching effect was observed for both ions. We have also investigated how by binding DNA the alkaloids could get protected from the external Co(2+) and Br(-) quenchers. The Stern-Volmer constants (K (SV)) for Co(2+) and Br(-) quenching effect on the studied alkaloids were considerably reduced (10-50%) after incubation of the compounds in the presence of DNA with regard to the K (SV) values in absence of DNA. An increase in the fluorescence anisotropy values of luotonins was also produced only in the presence of ds-DNA but not in the case of ss-DNA. To better characterize the nature of that interaction, viscosimetry assays and ethidium bromide displacement studies were conducted. With regard to DNA reference solutions, the viscosity of solutions containing DNA and luotonin A derivatives was reduced or not significantly increased. It was also observed that the studied compounds were unable to displace the intercalating agent ethidium bromide. All of these results, together with the obtained association constants values (K (ass) = 2.2 × 10(2) - 1.3 × 10(3)), support that neither covalent nor intercalating interactions luotonin A derivatives/ds-DNA are produced, leading to the conclusion that these alkaloids bind ds-DNA through the minor groove. The specific changes in the fluorescence behavior of luotonin A and derivatives distinguishing between ss-DNA and ds-DNA binding, lead us to propose these compounds as attractive turn-off probes to detect DNA hybridization.