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1.  Synthesis and Characterisation of Copper(II) Complexes with Tridentate NNO Functionalized Ligand: Density Function Theory Study, DNA Binding Mechanism, Optical Properties, and Biological Application 
The photo physical properties of two mononuclear pentacoordinated copper(II) complexes formulated as [Cu(L)(Cl)(H2O)] (1) and [Cu(L)(Br)(H2O)] (2) HL = (1-[(3-methyl-pyridine-2-ylimino)-methyl]-naphthalen-2-ol) were synthesized and characterized by elemental, physicochemical, and spectroscopic methods. The density function theory calculations are used to investigate the electronic structures and the electronic properties of ligand and complex. The interactions of copper(II) complexes towards calf thymus DNA were examined with the help of absorption, viscosity, and fluorescence spectroscopic techniques at pH 7.40. All spectroscopy's result indicates that complexes show good binding activity to calf thymus DNA through groove binding. The optical absorption and fluorescence emission properties of microwires were characterized by fluorescence microscope. From a spectroscopic viewpoint, all compounds strongly emit green light in the solid state. The microscopy investigation suggested that microwires exhibited optical waveguide behaviour which are applicable as fluorescent nanomaterials and can be used as building blocks for miniaturized photonic devices. Antibacterial study reveals that complexes are better antimicrobial agents than free Schiff base due to bacterial cell penetration by chelation. Moreover, the antioxidant study of the ligand and complexes is evaluated by using 1,1-diphenyl-2-picrylhydrazyl (DPPH) free-radical assays, which demonstrate that the complexes are of higher antioxidant activity than free ligand.
doi:10.1155/2014/104046
PMCID: PMC4214117  PMID: 25386109
2.  New Dihydro OO′Bis(Salicylidene) 2,2′ Aminobenzothiazolyl Borate Complexes: Kinetic and Voltammetric Studies of Dimethyltin Copper Complex with Guanine, Adenine, and Calf Thymus DNA 
The newly synthesized ligand, dihydro OO′bis(salicylidene) 2,2′ aminobenzothiazolyl borate (2), was derived from the reaction of Schiff base of 2-aminobenzothiazole and salicylaldehyde with KBH4. CuII (3) and ZnII (4) complexes of (2) were synthesized and further metallated with dimethyltindichloride to yield heterobimetallic complexes (5) and (6). All complexes have been thoroughly characterized by elemental analysis, and IR, NMR, EPR, and UV-Vis spectroscopy and conductance measurements. The spectroscopic data support square planar environment around the CuII atom, while the SnIV atom acquires pentacoordinate geometry. The interaction of complex (5) with guanine, adenine, and calf thymus DNA was studied by spectrophotometric, electrochemical, and kinetic methods. The absorption spectra of complex (5) exhibit a remarkable “hyperchromic effect” in the presence of guanine and calf thymus DNA. Indicative of strong binding of the complex to calf thymus DNA preferentially binds through N7 position of guanine base, while the adenine shows binding to a lesser extent. The kinetic data were obtained from the rate constants, kobs, values under pseudo-first-order conditions. Cyclic voltammetry was employed to study the interaction of complex (5) with guanine, adenine, and calf thymus DNA. The CV of complex (5) in the absence and in the presence of guanine and calf thymus DNA altered drastically, with a positive shift in formal peak potential Epa and Epc values and a significant increase in peak current. The positive shift in formal potentials with increase in peak current favours strong interaction of complex (5) with calf thymus DNA. The net shift in E1/2 has been used to estimate the ratio of equilibrium constants for the binding of Cu(II) and Cu(I) complexes to calf thymus DNA.
doi:10.1155/BCA/2006/32896
PMCID: PMC1686294  PMID: 17497007
3.  DNA Binding and Photocleavage Studies of Cobalt(III) Polypyridine Complexes: [Co(en)2PIP]3+, [Co(en)2IP]3+, and [Co(en)2phen-dione]3+ 
In this paper, three complexes of type [Co(en)2PIP]3+(PIP=2-phenylimidazo[4,5-f][1,10,] phenanthroline)(1), [Co(en)2IP]3+ (IP = imidazo[4,5-f][1,10,] phenanthroline)(2), and [Co(en)2phen-dione]3+(1,10 phenanthroline 5,6,dione)(3) have been synthesized and characterized by UV/VIS, IR, 1H NMR spectral methods. Absorption spectroscopy, emission spectroscopy, viscosity measurements, and DNA melting techniques have been used for investigating the binding of these two complexes with calf thymus DNA, and photocleavage studies were used for investigating these binding of these complexes with plasmid DNA. The spectroscopic studies together with viscosity measurements and DNA melting studies support that complexes 1 and 2 bind to CT DNA (= calf thymus DNA) by intercalation mode via IP or PIP into the base pairs of DNA, and complex 3 is binding as groove mode. Complex 1 binds more avidly to CT DNA than 2 and 3 which is consistent with the extended planar ring π system of PIP. Noticeably, the two complexes have been found to be efficient photosensitisers for strand scissions in plasmid DNA.
doi:10.1155/2007/54562
PMCID: PMC1997276  PMID: 18253471
4.  Studies of the Interaction between Isoimperatorin and Human Serum Albumin by Multispectroscopic Method: Identification of Possible Binding Site of the Compound Using Esterase Activity of the Protein 
The Scientific World Journal  2013;2013:305081.
Isoimperatorin is one of the main components of Prangos ferulacea as a linear furanocoumarin and used as anti-inflammatory, analgesic, antispasmodic, and anticancer drug. Human serum albumin (HSA) is a principal extracellular protein with a high concentration in blood plasma and carrier for many drugs to different molecular targets. Since the carrying of drug by HSA may affect on its structure and action, we decided to investigate the interaction between HSA and isoimperatorin using fluorescence and UV spectroscopy. Fluorescence data indicated that isoimperatorin quenches the intrinsic fluorescence of the HSA via a static mechanism and hydrophobic interaction play the major role in the drug binding. The binding average distance between isoimperatorin and Trp 214 of HSA was estimated on the basis of the theory of Förster energy transfer. Decrease of protein surface hydrophobicity (PSH) was also documented upon isoimperatorin binding. Furthermore, the synchronous fluorescence spectra show that the microenvironment of the tryptophan residues does not have obvious changes. Site marker compettive and fluorescence experiments revealed that the binding of isoimperatorin to HSA occurred at or near site I. Finally, the binding details between isoimperatorin and HSA were further confirmed by molecular docking and esterase activity inhibition studies which revealed that drug was bound at subdomain IIA.
doi:10.1155/2013/305081
PMCID: PMC3844181  PMID: 24319355
5.  DNA Interaction Studies of a New Platinum(II) Complex Containing Different Aromatic Dinitrogen Ligands 
A new mononuclear Pt(II) complex, [Pt(DMP)(DIP)]Cl2.H2O, in which DMP is 4,4-dimethyl-2,2-bipyridine and DIP is 4,7-diphenyl-1,10-phenantroline, has been synthesized and characterized by physicochemical and spectroscopic methods. The binding interaction of this complex with calf thymus DNA (CT-DNA) was investigated using fluorimetry, spectrophotometry, circular dichroism, viscosimetry and cyclic voltametry (CV). UV-VIS spectrum showed 4 nm bathochromic shift of the absorption band at 280 nm along with significant hypochromicity for the absorption band of the complex. The intrnisic binding constant (Kb = 2 × 104 M−1) is more in keeping with intercalators and suggests this binding mode. The viscosity measurements showed that the complex-DNA interaction can be hydrophobic and confirm intercalation. Moreover, the complex induced detectable changes in the CD spectrum of CT-DNA. The fluorescence studies revealed that the probable quenching mechanism of fluorescence of the complex by CT-DNA is static quenching. The thermodynamic parameters (ΔH > 0 and ΔS > 0) showed that main interaction with hydrogenic forces occurred that is intercalation mode. Also, CV results confirm this mode because, with increasing the CT-DNA concentration, shift to higher potential was observed.
doi:10.1155/2011/429241
PMCID: PMC3246310  PMID: 22216016
6.  Binding of Bacteriocin Clo DF13 to Clo DF13 Plasmid Deoxyribonucleic Acid In Vivo and In Vitro 
The bacteriocinogenic plasmid Clo DF13 is present in Escherichia coli to the extent of 10 copies per cell. A complex of Clo DF13 plasmid deoxyribonucleic acid (DNA) and protein can be isolated from cells. Treatment of the complex with ionic detergents or proteases dissociates the complex but does not convert any supercoiled Clo DF13 DNA to the open circular form, indicating that this complex is not a relaxation complex. The complex is stable in 0.5 M NaCl and contains one polypeptide species. The protein, present in the complex, appeared to be bacteriocin Clo DF13 for the following reasons: (i) the protein is de novo synthesized in Clo DF13-harboring minicells, indicating that this protein is Clo DF13 specific; (ii) this protein shows bacteriocinogenic activity on a bacteriocin Clo DF13-susceptible indicator strain; (iii) this protein has the same molecular weight (60,000) as bacteriocin Clo DF13. DNA-protein binding experiments, involving QAE-Sephadex column chromatography and nitrocellulose membrane filters, demonstrate that bacteriocin Clo DF13 has also affinity in vitro for Clo DF13 DNA. Membrane filter binding experiments revealed that bacteriocin Clo DF13 does not interact with other DNA species, such as ColE1 DNA, yeast DNA, calf thymus DNA, φX174 DNA, and also not with denatured Clo DF13 DNA. In addition no binding to Clo DF13 DNA of a related bacteriocin, colicin E3, could be detected. These results indicate that the binding of bacteriocin Clo DF 13 to double-stranded Clo DF13 DNA is very specific.
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PMCID: PMC429318  PMID: 1101824
7.  Spectroscopic studies of the multiple binding modes of a trimethine-bridged cyanine dye with DNA 
Nucleic Acids Research  2003;31(10):2561-2569.
The interaction between DNA and a benzothiazole-quinoline cyanine dye with a trimethine bridge (TO-PRO-3) results in the formation of three noncovalent complexes. Unbound TO-PRO-3 has an absorption maximum (λmax) of 632 nm, while the bound dyes (with calf thymus DNA) have electronic transitions with λmax = 514 nm (complex I), 584 nm (complex II) and 642 nm (complex III). The blue shifts in the electronic transitions and the bisignate shape of the circular dichroism bands indicate that TO-PRO-3 aggregates with DNA. Complex I has a high dye:base pair stoichiometry, which does not depend on base sequence or base modifications. The bound dyes exhibit strong interdye coupling, based on studies with a short oligonucleotide and on enhanced resonance scattering. From thermal dissociation studies, the complex is weakly associated with DNA. Studies with poly(dGdC)2 and poly(dIdC)2 and competitive binding with distamycin demonstrate that complex II is bound in the minor groove. This complex stabilizes the helix against dissociation. For complex III, the slightly red-shifted electronic transition and the stoichiometry are most consistent with intercalation. Using poly(dAdT)2, the complexes have the following dye mole fractions (Xdye): Xdye = 0.65 (complex I), 0.425 (complex II) and 0.34 (complex III).
PMCID: PMC156045  PMID: 12736305
8.  DNA Binding and Photocleavage Studies of Cobalt(III) Ethylenediamine Pyridine Complexes: [Co(en)2(py)2]3+ and [Co(en)2(mepy)2]3+ 
Metal-Based Drugs  2007;2008:275084.
Two novel cobalt(III) pyridine complexes (1) [Co(en)2(py)2]3+ and (2) [Co(en)2(mepy)2]3+ (en=ethylenediamine, py=pyridine, and mepy=methylpyridine) have been synthesized and characterized. The interaction of these complexes with calf thymus DNA was investigated by absorption, emission spectroscopy, viscosity measurements, DNA melting, and DNA photocleavage. Results suggest that the two complexes bind to DNA via groove mode and complex 2 binds more strongly to CT DNA than complex 1. Moreover, these Co(III) complexes have been found to promote the photocleavage of plasmid DNA pBR322 under irradiation at 365 nm, cytotoxicity results of complexes are also showing anticancer activity.
doi:10.1155/2008/275084
PMCID: PMC2225500  PMID: 18274660
9.  Identification of Binding Mode of a Platinum (II) Complex, PtCl2(DIP), and Calf Thymus DNA 
The Pt(II) complex, PtCl2(DIP) (DIP = chelating dinitrogen ligand: 4,7-diphenyl-1,10-phenanthroline), was synthesized and characterized by elemental analysis (CHN) and 1H NMR and UV-vis techniques. The binding of this complex to calf thymus DNA was investigated using various physicochemical methods such as spectrophotometric, circular dichroism, spectrofluorometric, melting temperature, and viscosimetric techniques. Upon addition of the complex, important changes were observed in the characteristic UV-Vis bands (hyperchromism) of calf thymus DNA (CT-DNA): increase in melting temperature, sharp increase in specific viscosity of DNA, and induced CD spectral changes. Also the fluorescence spectral characteristics and interaction of Pt complex with DNA have been studied. Pt bound to DNA showed a marked decrease in the fluorescence intensity. The results show that both the complex and the NR molecules can intercalate competitively into the DNA double-helix structure. The experimental results show that the mode of binding of the this complex to DNA is classical intercalation.
doi:10.1155/2011/687571
PMCID: PMC3202101  PMID: 22110411
10.  DNA Interaction and DNA Cleavage Studies of a New Platinum(II) Complex Containing Aliphatic and Aromatic Dinitrogen Ligands 
A new Pt(II) complex, [Pt(DIP)(LL)](NO3)2 (in which DIP is 4,7-diphenyl-1,10-phenanthroline and LL is the aliphatic dinitrogen ligand, N,N-dimethyl-trimethylenediamine), was synthesized and characterized using different physico-chemical methods. The interaction of this complex with calf thymus DNA (CT-DNA) was investigated by absorption, emission, circular dichroism (CD), and viscosity measurements. The complex binds to CT-DNA in an intercalative mode. The calculated binding constant, Kb, was 6.6 × 104 M−1. The enthalpy and entropy changes of the reaction between the complex and CT-DNA showed that the van der Waals interactions and hydrogen bonds are the main forces in the interaction with CT-DNA. In addition, CD study showed that phenanthroline ligand insert between the base pair stack of double helical structure of DNA. It is remarkable that this complex has the ability to cleave the supercoiled plasmid.
doi:10.1155/2011/525794
PMCID: PMC3253441  PMID: 22235195
11.  Co(III) and Ni(II) Complexes Containing Bioactive Ligands: Synthesis, DNA Binding, and Photocleavage Studies 
DNA binding and photocleavage characteristics of a series of mixed ligand complexes of the type [M(bpy)2qbdp](PF6)n·xH2O (where M = Co(III) or Ni(II), bpy = 2.2′-bipryidine, qbdp = Quinolino[3,2-b]benzodiazepine, n = 3 or 2 and x = 5 or 2) have been investigated. The DNA binding property of the complexes with calf thymus DNA has been investigated by using absorption spectra, viscosity measurements, as well as thermal denaturation studies. Intrinsic binding constant (Kb) has been estimated under similar set of experimental conditions. Absorption spectral studies indicate that the Co(III) and Ni(II) complexes intercalate between the base pairs of the CT-DNA tightly with intrinsic DNA binding constant of 1.3 × 106 and 3.1 × 105 M−1 in Tris-HCl buffer containing 50 mM NaCl, respectively. The proposed DNA binding mode supports the large enhancement in the relative viscosity of DNA on binding to quinolo[3,2-b]benzodiazepine. The oxidative as well as photo-induced cleavage reactions were monitered by gel electrophoresis for both complexes. The photocleavage experiments showed that the cobalt(III) complex can cleave pUC19 DNA effectively in the absence of external additives as an effective inorganic nuclease.
doi:10.1155/2007/36497
PMCID: PMC1876624  PMID: 17541480
12.  Interaction of 6 Mercaptopurine with Calf Thymus DNA – Deciphering the Binding Mode and Photoinduced DNA Damage 
PLoS ONE  2014;9(4):e93913.
DNA is one of the major intracellular targets for a wide range of anticancer and antibiotic drugs. Elucidating the binding between small molecules and DNA provides great help in understanding drug-DNA interactions and in designing of new and promising drugs for clinical use. The ability of small molecules to bind and interfere with DNA replication and transcription provides further insight into how the drugs control the expression of genes. Interaction of an antimetabolite anticancer drug 6mercaptopurine (6MP) with calf thymus DNA was studied using various approaches like UV-visible spectroscopy, fluorescence spectroscopy, CD, viscosity and molecular docking. UV-visible spectroscopy confirmed 6MP-DNA interaction. Steady state fluorescence experiments revealed a moderate binding constant of 7.48×103 M−1 which was consistent with an external binding mode. Competitive displacement assays further confirmed a non-intercalative binding mode of 6MP which was further confirmed by CD and viscosity experiments. Molecular docking further revealed the minimum energy conformation (−119.67 kJ/mole) of the complex formed between DNA and 6MP. Hence, the biophysical techniques and in-silico molecular docking approaches confirmed the groove binding/electrostatic mode of interaction between 6MP and DNA. Further, photo induced generation of ROS by 6MP was studied spectrophotometrically and DNA damage was assessed by plasmid nicking and comet assay. There was a significant increase in ROS generation and consequent DNA damage in the presence of light.
doi:10.1371/journal.pone.0093913
PMCID: PMC3981731  PMID: 24718609
13.  Formation of Stable and Metastable Porphyrin- and Corrole-Iron(IV) Complexes and Isomerizations to Iron(III) Macrocycle Radical Cations 
Journal of inorganic biochemistry  2008;103(2):174-181.
Oxidations of three porphyrin-iron(III) complexes (1) with ferric perchlorate, Fe(ClO4)3, in acetonitrile solutions at −40 °C gave metastable porphyrin-iron(IV) diperchlorate complexes (2) that isomerized to known iron(III) diperchlorate porphyrin radical cations (3) when the solutions were warmed to room temperature. The 5,10,15,20-tetraphenylporphyrin (TPP), 5,10,15,20-tetramesitylporphyrin (TMP), and 2,3,7,8,12,13,17,18-octaethylporphyrin (OEP) systems were studied by UV-visible spectroscopy. Low temperature NMR spectroscopy and effective magnetic moment measurements were possible with the TPP and TMP iron(IV) complexes. Reactions of two corrole systems, 5,10,15-tris(pentafluorophenyl)corrole (TPFC) and 5,15-bis(pentafluorophenyl)-10-p-methoxyphenylcorrole (BPFMC), also were studied. The corrole-iron(IV) chlorides reacted with silver salts to give corrole-iron(IV) complexes. The corrole-iron(IV) nitrate complexes were stable at room temperature. (TPFC)-iron(IV) toslyate, (TPFC)-iron(IV) chlorate, and (BPFMC)-iron(IV) chlorate were metastable and rearranged to their electronic isomers iron(III) corrole radical cations at room temperature. (TPFC)-iron(III) perchlorate corrole radical cation was the only product observed from reaction of the corrole-iron(IV) chloride with silver perchlorate. For the metastable iron(IV) species, the rates of isomerizations to the iron(III) macrocycle radical cation electronic isomers in dilute acetonitrile solutions were relatively insensitive to electron demands of the macrocyclic ligand but reflected the binding strength of the ligand to iron. Kinetic studies at varying temperatures and concentrations indicated that the mechanisms of the isomerization reactions are complex, involving mixed order reactivity.
doi:10.1016/j.jinorgbio.2008.09.017
PMCID: PMC2680251  PMID: 19013647
high-valent; iron; porphyrin; corrole; oxidation; isomerization; valence tautomer
14.  Initial DNA Interactions of the Binuclear Threading Intercalator Λ,Λ-[μbidppz(bipy)4Ru2]4+: An NMR Study with [d(CGCGAATTCGCG)]2** 
Binuclear polypyridine ruthenium compounds have been shown to slowly intercalate into DNA, following a fast initial binding on the DNA surface. For these compounds, intercalation requires threading of a bulky substituent, containing one RuII, through the DNA base-pair stack, and the accompanying DNA duplex distortions are much more severe than with intercalation of mononuclear compounds. Structural understanding of the process of intercalation may greatly gain from a characterisation of the initial interactions between binuclear RuII compounds and DNA. We report a structural NMR study on the binuclear RuII intercalator Λ,Λ-B (Λ,Λ-[μ-bidppz(bipy)4Ru2]4+; bidppz=11,11′-bis(dipyrido[3,2-a:2′,3′-c]phenazinyl, bipy = 2,2′-bipyridine) mixed with the palindromic DNA [d(CGCGAATTCGCG)]2. Threading of Λ,Λ-B depends on the presence and length of AT stretches in the DNA. Therefore, the latter was selected to promote initial binding, but due to the short stretch of AT base pairs, final intercalation is prevented. Structural calculations provide a model for the interaction: Λ,Λ-B is trapped in a well-defined surface-bound state consisting of an eccentric minor-groove binding. Most of the interaction enthalpy originates from electrostatic and van der Waals contacts, whereas intermolecular hydrogen bonds may help to define a unique position of Λ,Λ-B. Molecular dynamics simulations show that this minor-groove binding mode is stable on a nanosecond scale. To the best of our knowledge, this is the first structural study by NMR spectroscopy on a binuclear Ru compound bound to DNA. In the calculated structure, one of the positively charged Ru2+ moieties is near the central AATT region; this is favourable in view of potential intercalation as observed by optical methods for DNA with longer AT stretches. Circular dichroism (CD) spectroscopy suggests that a similar binding geometry is formed in mixtures of Λ,Λ-B with natural calf thymus DNA. The present minor-groove binding mode is proposed to represent the initial surface interactions of binuclear RuII compounds prior to intercalation into AT-rich DNA.
doi:10.1002/chem.201203175
PMCID: PMC3743166  PMID: 23447081
DNA; intercalation; minor-groove binding; NMR spectroscopy; ruthenium
15.  Groove-binding unsymmetrical cyanine dyes for staining of DNA: syntheses and characterization of the DNA-binding 
Nucleic Acids Research  2003;31(21):6227-6234.
Two new crescent-shaped unsymmetrical cyanine dyes have been synthesised and their interactions with DNA have been investigated by different spectroscopic methods. These dyes are analogues to a minor groove binding unsymmetrical cyanine dye, BEBO, recently reported by us. In this dye, the structure of the known intercalating cyanine dye BO was extended with a benzothiazole substituent. To investigate how the identity of the extending heterocycle affects the binding to DNA, the new dyes BETO and BOXTO have a benzothiazole group and a benzoxazole moiety, respectively. Whereas BEBO showed a heterogeneous binding to calf thymus DNA, linear and circular dichroism studies of BOXTO indicate a high preference for minor groove binding. BETO also binds in the minor groove to mixed sequence DNA but has a contribution of non-ordered and non-emissive species present. A non-intercalative binding mode of the new dyes, as well as for BEBO, is further supported by electrophoresis unwinding assays. These dyes, having comparable spectral properties as the intercalating cyanine dyes, but bind in the minor groove instead, might be useful complements for staining of DNA. In particular, the benzoxazole substituted dye BOXTO has attractive fluorescence properties with a quantum yield of 0.52 when bound to mixed sequence DNA and a 300-fold increase in fluorescence intensity upon binding.
doi:10.1093/nar/gkg821
PMCID: PMC275463  PMID: 14576310
16.  Study on the Interaction between Isatin-β-Thiosemicarbazone and Calf Thymus DNA by Spectroscopic Techniques 
The interaction between isatin-β-thiosemicarbazone (IBT) and calf thymus DNA (CT-DNA) was investigated in physiological buffer (pH 7.4) using Neutral Red (NR) dye as a spectral probe by UV–Vis absorption and fluorescence spectroscopy, as well as viscosity measurements. The IBT is stabilized by intercalation in the DNA (K [IBT –DNA] = 1.03×105 M−1), and displaces the NR dye from the NR–DNA complex. The binding constants Kf and number of binding sites (n≈1) of IBT with DNA were obtained by fluorescence quenching method at different temperatures. Furthermore, the enthalpy and entropy of the reaction between IBT and CT-DNA showed that the reaction is enthalpy-favored and entropy-disfavored. The changes in the base stacking of CT-DNA upon the binding of IBT are reflected in the circular dichroic (CD) spectral studies. The viscosity increase of CT-DNA solution is another evidence to indicate that, IBT is able to be intercalated in the DNA base pairs.
PMCID: PMC4277624  PMID: 25561917
CT-DNA; Isatin-β-thiosemicarbazone; Neutral Red dye; Intercalation
17.  The different binding modes of Hoechst 33258 to DNA studied by electric linear dichroism. 
Nucleic Acids Research  1993;21(16):3705-3709.
The binding mode of the bisbenzimidazole derivative Hoechst 33258 to a series of DNAs and polynucleotides has been investigated by electric linear dichroism. Positive reduced dichroisms were measured for the poly(dA-dT).poly(dA-dT)- and poly(dA).poly(dT)-Hoechst complexes in agreement with a deep penetration of the drug into the minor groove. Similarly, the drug displays positive reduced dichroism in the presence of the DNAs from calf thymus, Clostridium perfringens and Coliphage T4. Conversely, negative reduced dichroisms were obtained when Hoechst 33258 was bound to poly(dG-dC).poly(dG-dC), poly(dA-dC).poly(dG-dT) and poly(dG).poly(dC) as well as with the GC-rich DNA from Micrococcus lysodeikticus indicating that in this case minor groove binding cannot occur. Substitution of guanosines for inosines induces a reversal of the reduced dichroism from negative to positive. Therefore, as anticipated it is the 2-amino group of guanines protruding in this groove which prevents Hoechst 33258 from getting access to the minor groove of GC sequences. The ELD data obtained with the GC-rich biopolymers are consistent with an intercalative binding. Competition experiments performed with the intercalating drug proflavine lend credence to the involvement of an intercalative binding rather than to an external or major groove binding of Hoechst 33258 at GC sequences.
PMCID: PMC309869  PMID: 7690125
18.  Structural analysis of DNA complexation with cationic lipids 
Nucleic Acids Research  2008;37(3):849-857.
Complexes of cationic liposomes with DNA are promising tools to deliver genetic information into cells for gene therapy and vaccines. Electrostatic interaction is thought to be the major force in lipid–DNA interaction, while lipid-base binding and the stability of cationic lipid–DNA complexes have been the subject of more debate in recent years. The aim of this study was to examine the complexation of calf-thymus DNA with cholesterol (Chol), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), dioctadecyldimethylammoniumbromide (DDAB) and dioleoylphosphatidylethanolamine (DOPE), at physiological condition, using constant DNA concentration and various lipid contents. Fourier transform infrared (FTIR), UV-visible, circular dichroism spectroscopic methods and atomic force microscopy were used to analyse lipid-binding site, the binding constant and the effects of lipid interaction on DNA stability and conformation. Structural analysis showed a strong lipid–DNA interaction via major and minor grooves and the backbone phosphate group with overall binding constants of KChol = 1.4 (±0.5) × 104 M−1, KDDAB = 2.4 (±0.80) × 104 M−1, KDOTAP = 3.1 (±0.90) × 104 M−1 and KDOPE = 1.45 (± 0.60) × 104 M−1. The order of stability of lipid–DNA complexation is DOTAP>DDAB>DOPE>Chol. Hydrophobic interactions between lipid aliphatic tails and DNA were observed. Chol and DOPE induced a partial B to A-DNA conformational transition, while a partial B to C-DNA alteration occurred for DDAB and DOTAP at high lipid concentrations. DNA aggregation was observed at high lipid content.
doi:10.1093/nar/gkn1003
PMCID: PMC2647290  PMID: 19103664
19.  Synthesis, Characterization, DNA Interaction, and Antitumor Activities of La (III) Complex with Schiff Base Ligand Derived from Kaempferol and Diethylenetriamine 
A novel La (III) complex, [LaL(H2O)3]NO3·3H2O, with Schiff base ligand L derived from kaempferol and diethylenetriamine, has been synthesized and characterized by elemental analysis, IR, UV-visible, 1H NMR, thermogravimetric analysis, and molar conductance measurements. The fluorescence spectra, circular dichroism spectra, and viscosity measurements and gel electrophoresis experiments indicated that the ligand L and La (III) complex could bind to CT-DNA presumably via intercalative mode and the La (III) complex showed a stronger ability to bind and cleave DNA than the ligand L alone. The binding constants (Kb) were evaluated from fluorescence data and the values ranged from 0.454 to 0.659 × 105 L mol−1 and 1.71 to 17.3 × 105 L mol−1 for the ligand L and La (III) complex, respectively, in the temperature range of 298–310 K. It was also found that the fluorescence quenching mechanism of EB-DNA by ligand L and La (III) complex was a static quenching process. In comparison to free ligand L, La (III) complex exhibited enhanced cytotoxic activities against tested tumor cell lines HL-60 and HepG-2, which may correlate with the enhanced DNA binding and cleaving abilities of the La (III) complex.
doi:10.1155/2014/354138
PMCID: PMC4209760  PMID: 25371657
20.  Synthesis of New Five Coordinated Copper(II) and Nickel(II) Complexes of L-Valine and Kinetic Study of Copper(II) with Calf Thymus DNA 
Metal-Based Drugs  2002;9(1-2):81-90.
Five coordinated novel complexes of Cu II and Ni II have been synthesized from benzil and 1,3- diaminopropane- Cu II / Ni II complex and characterized by elemental analysis, i.r., n.m.r., e.p.r, molar conductance and u.v-vis, spectroscopy. The complexes are ionic in nature and exhibit pentaeoordinated geometry around the metal ion. The reaction kinetics of C 25 H 36 N 5 O 2 CuCl with calf thymus DNA was studied by u.v-vis, spectroscopy in aqueous medium. The complex after interaction with calf thymus DNA shows shift in the absorption spectrum and hypochromicity indicating an intercalative binding mode. The K obs values have been calculated under pseudo-first order conditions. The redox behaviour of complex C 25 H 36 N 5 O 2 CuCl in the presence and in the absence of calf thymus DNA in the aqueous solution has been investigated by cyclic voltammetry. The cyclic voitammogram exhibits one quasi-reversible redox wave corresponding to Cu II / Cu I redox couple with E 1 / 2 values of -0.377 and -0.237 V respectively at a scan rate of 0.1V s - 1 .On interaction with calf thymus DNA, the complex C 25 H 36 N 5 O 2 CuCl exhibits shifts in both E p as well as in E 1 / 2 values, indicating strong binding of the complex to the calf thymus DNA.
doi:10.1155/MBD.2002.81
PMCID: PMC2365303  PMID: 18475428
21.  Binding of Hoechst 33258 to the TAR RNA of HIV-1. Recognition of a pyrimidine bulge-dependent structure. 
Nucleic Acids Research  1997;25(22):4487-4492.
The transactivation response region (TAR) RNA is an essential component in transcriptional regulation of the human immunodeficiency virus type-1 (HIV-1) genome. We have examined the interaction between TAR RNA and the bisbenzimidazole derivative Hoechst 33258. Previous studies have shown that this drug, which is well known as an AT-selective DNA minor groove binder, can also interact with GC-rich sequences in DNA as well as with RNA, possibly by intercalation. Absorption spectroscopy, circular dichroism and electric linear dichroism, as well as RNase A footprinting, were employed to compare binding of Hoechst 33258 to wild-type RNA and its analogue lacking the pyrimidine bulge. The uridine bulge, which is an important contributor to the structural stability of TAR, plays an essential role in drug binding. Deletion of the bulge destabilizes both free and drug-bound forms of TAR and markedly affects the orientation of the drug chromophore complexed with the RNA. According to the linear dichroism data, the bisbenzimidazole is oriented more or less perpendicular to the RNA helix axis. The data are compatible with a model in which the bisbenzimidazole chromophore is inserted into the existing cavity created by the pyrimidine bulge. The footprinting experiments, showing that the drug binds to a unique site opposite the unpaired uridine residues, also support this model. The binding of Hoechst 33258 to the sequence 5'-GCUCU, which delimits the cavity, reflects the greater accessibility of that region compared with other sites in the RNA molecule. The identification of a binding site for small molecules in TAR offers promising perspectives for developing drugs that would block the access of TAR RNA to proteins and therefore for the design of anti-HIV agents.
PMCID: PMC147084  PMID: 9358156
22.  Proton Control of Oxidation and Spin State in a Series of Iron Tripodal Imidazole Complexes 
Inorganic chemistry  2004;43(7):2402-2415.
Reaction of iron salts with three tripodal imidazole ligands, H3(1), H3(2), H3(3), formed from the condensation of tris(2-aminoethyl)amine (tren) with 3 equiv of an imidazole carboxaldehyde yielded eight new cationic iron(III) and iron(II), [FeH3L]3+or2+, and neutral iron(III), FeL, complexes. All complexes were characterized by EA(CHN), IR, UV, Mössbauer, mass spectral techniques and cyclic voltammetry. Structures of three of the complexes, Fe(2)·3H2O (C18H27FeN10O3, a = b = c = 20.2707(5), cubic, I4̄3d, Z = 16), Fe(3)·4.5H2O (C18H30FeN10O4.5, a = 20.9986(10), b = 11.7098(5), c = 19.9405(9), β= 109.141(1), monoclinic, P2(1)/c), Z = 8), and [FeH3(3)](ClO4)2·H2O (C18H26Cl2FeN10O9, a = 9.4848(4), b = 23.2354(9), c = 12.2048(5), β= 111.147(1)°, monoclinic, P2(1)/n, Z = 4) were determined at 100 K. The structures are similar to one another and feature an octahedral iron with facial coordination of imidazoles and imine nitrogen atoms. The iron(III) complexes of the deprotonated ligands, Fe(1), Fe(2), and Fe(3), are low-spin while the protonated iron(III) cationic complexes, [FeH3(1)](ClO4)3 and [FeH3(2)](ClO4)3, are high-spin and spin-crossover, respectively. The iron(II) cationic complexes, [FeH3(1)]S4O6, [FeH3(2)](ClO4)2, [FeH3(3)](ClO4)2, and [FeH3(3)][B(C6H5)4]2 exhibit spin-crossover behavior. Cyclic voltammetric measurements on the series of complexes show that complete deprotonation of the ligands produces a negative shift in the Fe(III)/Fe(II) reduction potential of 981 mV on average. Deprotonation in air of either cationic iron(II) or iron(III) complexes, [FeH3L]3+or2+, yields the neutral iron(III) complex, FeL. The process is reversible for Fe(3), where protonation of Fe(3) yields [FeH3(3)]2+.
doi:10.1021/ic0351747
PMCID: PMC1995556  PMID: 15046517
23.  Role of Minor Groove Width and Hydration Pattern on Amsacrine Interaction with DNA 
PLoS ONE  2013;8(7):e69933.
Amsacrine is an anilinoacridine derivative anticancer drug, used to treat a wide variety of malignancies. In cells, amsacrine poisons topoisomerase 2 by stabilizing DNA-drug-enzyme ternary complex. Presence of amsacrine increases the steady-state concentration of these ternary complexes which in turn hampers DNA replication and results in subsequent cell death. Due to reversible binding and rapid slip-out of amsacrine from DNA duplex, structural data is not available on amsacrine-DNA complexes. In the present work, we designed five oligonucleotide duplexes, differing in their minor groove widths and hydration pattern, and examined their binding with amsacrine using attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy. Complexes of amsacrine with calf thymus DNA were also evaluated for a comparison. Our results demonstrate for the first time that amsacrine is not a simple intercalator; rather mixed type of DNA binding (intercalation and minor groove) takes place between amsacrine and DNA. Further, this binding is highly sensitive towards the geometries and hydration patterns of different minor grooves present in the DNA. This study shows that ligand binding to DNA could be very sensitive to DNA base composition and DNA groove structures. Results demonstrated here could have implication for understanding cytotoxic mechanism of aminoacridine based anticancer drugs and provide directions to modify these drugs for better efficacy and few side-effects.
doi:10.1371/journal.pone.0069933
PMCID: PMC3726726  PMID: 23922861
24.  Cytotoxic Hydrophilic Iminophosphorane Coordination Compounds of d8 Metals. Studies of their Interactions with DNA and HSA 
The synthesis and characterization of a new water-soluble N,N-chelating iminophosphorane ligand TPA=N-C(O)-2-NC5H4 (N,N-IM) (1) and its d8 (AuIII, PdII and PtII) coordination complexes are reported. The structures of cationic [AuCl2(N,N-IM)] ClO4 (2) and neutral [MCl2(N,N-IM)] M = Pd (3), Pt(4) complexes were determined by X-ray diffraction studies or by means of density-functional calculations. While the Pd and Pt compounds are stable in mixtures of DMSO/H2O over 4 days, the gold derivative (2) decomposes quickly to TPA=O and previously reported neutral gold(III) compound [AuCl2(N,N-H)] 5 (containing the chelating N,N- fragment HN-C(O)-2-NC5H4). The cytotoxicities of complexes 2–5 were evaluated in vitro against human Jurkat-T acute lymphoblastic leukemia cells and DU-145 human prostate cancer cells. Pt (4) and Au compounds (2 and 5) are more cytotoxic than cisplatin to these cell lines and to cisplatin-resistant Jurkat sh-Bak cell lines and their cell death mechanism is different from that of cisplatin. All the compounds show higher toxicity against leukemia cells when compared to normal human T-lymphocytes (PBMC). The interaction of the Pd and Pt compounds with calf thymus and plasmid (pBR322) DNA is different from that of cisplatin. All compounds bind to human serum albumin (HSA) faster than cisplatin (measured by fluorescence spectroscopy). Weak and stronger binding interactions were found for the Pd (3) and Pt (4) derivatives by isothermal titration calorimetry. Importantly, for the Pt (4) compounds the binding to HSA was reversed by addition of a chelating agent (citric acid) and by a decrease in pH.
doi:10.1016/j.jinorgbio.2012.06.017
PMCID: PMC3483362  PMID: 23063789
cytotoxic; leukemia; prostate cancer; iminophosphoranes; water-soluble; platinum; palladium; gold
25.  Macrocyclic Diamide Ligand Systems: Potential Chelators for 64Cu- and 68Ga-Based Positron Emission Tomography Imaging Agents 
Inorganic chemistry  2009;48(15):7117-7126.
The N4-macrocyclic ligand 2,10-dioxo-1,4,8,11-tetraazabicyclo[11.4.0]1,12-heptadeca-1(12),14,16-triene H2L has been synthesized by the [1 + 1] condensation reaction between N,N′-bis(chloroacetyl)-1,2-phenylenediamine and 1,3-propylenediamine. The coordination chemistry of this ligand has been investigated with the metal ions Cu (II), Ni(II), Zn(II), and Ga(III) (complexes 1, 2, 3 and 4, respectively). H2L and its metal complexes have been fully characterized by the use of NMR, UV/vis, electron paramagnetic resonance, and elemental analysis where appropriate. The four metal complexes 1–4 have been structurally characterized by X-ray crystallography which confirmed that in all cases the amide nitrogen atoms are deprotonated and coordinated to the metal center. Complexes 3 and 4 are five-coordinate with a water molecule and chloride ion occupying the apical site, respectively. Cyclic voltammetric measurements on complex 1 show that this complex is oxidized reversibly with a half-wave potential, E1/2 = 0.47 V, and reduced irreversibly at EP = −1.84 V. Density functional theory calculations reproduce the geometries of the four complexes. The one-electron reduction and oxidation potentials for 1 were calculated by using two solvent models, DMF and H2O. The calculations indicated that the one electron oxidation of 1 may involve removal of an electron from the ligand as opposed to the metal center, producing a diradical. The diamide macrocyle is of interest for the development of new positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging agents, and a radiolabeled complex has been synthesized with the positron emitting isotope 64Cu. In vivo biodistribution studies for the 64Cu labeled complex, 64Cu-1, in male Lewis rats, showed that the activity is cleared rapidly from the blood within 1–2 h post-administration.
doi:10.1021/ic900307f
PMCID: PMC4287963  PMID: 19588930

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