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1.  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
2.  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
3.  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
4.  Luminescence of ruthenium(II) polypyridyls: evidence for intercalative binding to Z-DNA. 
Nucleic Acids Research  1991;19(10):2595-2602.
Photophysical studies have been undertaken to characterize the binding interactions of enantiomers of Ru(phen)3(2+), Ru(DIP)3(2+), and racemic Ru(bpy)2dppz2+ (where phen = 1,10-phenanthroline, DIP = 4,7-diphenylphenanthroline, and dppz = dipyridophenazine) with Z-form poly d(GC). Parallel enhancements in steady state luminescent intensity and a lengthening of luminescent lifetimes are seen for ruthenium enantiomers with Z-DNA as for B-DNA but with enantioselectivities reversed. Greater enhancements are seen for delta-isomers with the right-handed helix but for lambda-isomers with the left-handed helix. Ru(bpy)2dppz2+, an avid intercalator in B-DNA, displays no luminescence free in aqueous solution, but luminesces brightly bound to either B- or Z-poly d(GC). Stern-Volmer quenching studies also support the enantioselective preference in binding to B-DNA by delta-isomers and a reversal with binding to Z-DNA preferentially by the lambda-isomers. Steady state polarization studies indicate a rigid association of the complexes with both B- and Z-DNA on the time-scale of their emission and again with symmetrical enantioselectivities for the left and right-handed helices. Given the well characterized intercalative association of the complexes with B-DNA, the parallel results seen here with Z-DNA point strongly to a comparable intercalative association with the Z-form helix. That molecules may interact with Z-DNA through intercalation has not been demonstrated previously and now requires consideration in describing the range of interactions of small molecules and proteins with Z-DNA.
PMCID: PMC328175  PMID: 2041736
5.  Binding of ethidium and bis(methidium)spermine to Z DNA by intercalation. 
Nucleic Acids Research  1984;12(11):4679-4690.
The interaction of ethidium bromide, a DNA intercalating drug, and bis( methidium )spermine, a DNA bis-intercalating compound, with the left-handed Z form of poly(dG-dC) has been studied in 4.4 M NaCl. Spectrophotometric analysis using absorption, fluorescence and circular dichroism indicates that the complex formed between ethidium and Z DNA resembles very closely that formed with B DNA. This suggests that ethidium binds to Z DNA by intercalation. 31P NMR spectra are presented showing both the conversion of the Z form to the B form with increasing amounts of drug and the typical Z form spectrum at low binding densities. Data are also presented which show that the bifunctional intercalator bis( methidium )spermine binds to Z DNA in a manner similar to its binding to B DNA, i.e., by bis-intercalation. These results are important for our understanding the behavior of Z DNA and its biological significance.
PMCID: PMC318867  PMID: 6739293
6.  Phototriggering Electron Flow through ReI-modified Pseudomonas aeruginosa Azurins 
The ReI(CO)3(4,7-dimethyl-1,10-phenanthroline)(histidine-124)(tryptophan-122) complex, denoted ReI(dmp)(W122), of Pseudomonas aeruginosa azurin behaves as a single photoactive unit that triggers very fast electron transfer (ET) from a distant (2 nm) CuI center in the protein. Analysis of time-resolved (ps-μs) IR spectroscopic and kinetics data collected on ReI(dmp)(W122)AzM (M = ZnII CuII, CuI; Az = azurin) and position-122 tyrosine (Y), phenylalanine (F), and lysine (K) mutants together with excited-state DFT/TDDFT calculations and X-ray structural characterization reveal the character, energetics, and dynamics of the relevant electronic states of the ReI(dmp)(W122) unit and a cascade of photoinduced ET and relaxation steps in the corresponding Re-azurins. Optical population of ReI(imidazole-H124)(CO)3→dmp 1CT states is followed by ~110 fs intersystem crossing and ~600 ps structural relaxation to a 3CT state whose IR spectrum indicates a mixed ReI(CO)3,A→dmp/π→π*(dmp) character for aromatic amino acids A122 (A = W, Y, F) and ReI(CO)3→dmp MLCT for ReI(dmp)(K122)AzCuII. In a few ns, the 3CT state of ReI(dmp)(W122)AzM establishes an equilibrium with the ReI(dmp•−)(W122•+)AzM charge-separated state, 3CS, whereas the 3CT state of the other Y, F, and K122 proteins decays to the ground state. In addition to this main pathway, 3CS is populated by fs and ps W(indole)→ReII ET from 1CT and the initially “hot” 3CT states, respectively. The 3CS state undergoes a tens-of-ns dmp•−→W122•+ ET recombination leading to the ground state or, in the case of the CuI azurin, competitively fast (~30 ns over 1.12 nm) CuI→W•+ ET producing ReI(dmp•−)(W122)AzCuII. The overall photoinduced CuI→Re(dmp) ET through ReI(dmp)(W122)AzCuI occurs over a 2 nm distance in <50 ns after excitation, the intervening fast 3CT-3CS equilibrium being the principal accelerating factor. No reaction was observed for the three Y, F, and K122 analogues. Although the presence of Re(dmp)(W122)AzCuII oligomers in solution was documented by mass spectrometry and phosphorescence anisotropy, kinetics data do not indicate any significant interference from intermolecular ET steps. The ground-state dmp-indole ππ interaction together with well-matched W/W•+ and excited-state ReII(CO)3(dmp•−)/ReI(CO)3(dmp•−) potentials, that result in very rapid electron interchange and 3CT - 3CS energetic proximity, are the main factors responsible for the unique ET behavior of ReI(dmp)(W122)-containing azurins.
doi:10.1002/chem.201002162
PMCID: PMC3108028  PMID: 21469225
7.  Interactions of DNA binding ligands with PNA-DNA hybrids. 
Nucleic Acids Research  1994;22(24):5371-5377.
The interactions of two representative mixed-sequence (one with an AT-stretch) PNA-DNA duplexes (10 or 15 base-pairs) and a PNA2/DNA triplex with the DNA binding reagents distamycin A, 4',6-diamidino-2-phenylindole (DAPI), ethidium bromide, 8-methoxy-psoralen and the delta and lambda enantiomers of Ru(phen)2-dppz2+ have been investigated using optical spectroscopic methods. The behaviour of these reagents versus two PNA-PNA duplexes has also been investigated. With triple helical poly(dA)/(H-T10-Lys-NH2)2 no significant intercalative binding was detected for any of the DNA intercalators, whereas DAPI, a DNA minor groove binder, was found to exhibit a circular dichroism with a positive sign and amplitude consistent with minor groove binding. Similarly, a PNA-DNA duplex containing a central AATA motif, a typical minor groove binding site for the DNA minor groove binders distamycin A and DAPI, showed binding for both of these drugs, though with strongly reduced affinity. No important interactions were found for any of the ligands with a PNA-DNA duplex consisting of a ten base-pair mixed purine-pyrimidine sequence with only two AT base-pairs in the centre. Nor did any of the ligands show any detectable binding to the PNA-PNA duplexes (one containing an AATT motif). Various PNA derivatives with extentions of the backbone, believed to increase the flexibility of the duplex to opening of an intercalation slot, were tested for intercalation of ethidium bromide or 8-methoxypsoralen into the mixed sequence PNA-DNA duplex, however, without any observation of improved binding. The importance of the ionic contribution of the deoxyribose phosphate backbone, versus interactions with the nucleobases, for drug binding to DNA is discussed in the light of these findings.
PMCID: PMC332085  PMID: 7816628
8.  A clarification of the complex spectrum observed with the ultraviolet circular dichroism of ethidium bromide bound to DNA. 
Nucleic Acids Research  1975;2(4):477-486.
Ethidium bromide intercalation strongly effects the circular dichroism spectrum of DNA in the region of 230-300 mu, in a complex manner. In this report we present a study that quantitizes the relationships of the circular dichroism spectrum in the region of 230-300 mu and the ethidium bromide induced optical activity centered around 308 mu. We present evidence of two hidden cooperative bands that are probably the negative counterparts of the 308 mu band and 330 mu shoulder positive cooperative bands. The hidden band is quantitatively characterized. We confirm that the direct effect of ethidium bromide on the DNA spectrum is simply linearly proportional to the amount of intercalated dye. We also observe that the ethidium bromide enters freely when there is a molecule intercalated for every 3 sites, but that the intercalation is more difficult when the molecule intercalates at every second site.
PMCID: PMC342856  PMID: 1138233
9.  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
10.  The Effects of Extending of Co-planarity in a Series of Structurally Relative Polypyridyl Palladium(II) Complexes on DNA-binding and Cytotoxicity Properties  
In depth interaction studies between calf thymus deoxyribonucleic acid (CT-DNA) and a series of four structurally relative palladium(II) complexes [Pd(en)(HB)](NO3)2 (a-d), where en is ethylenediamine and heterocyclic base (HB) is 2,2'-bipyridine (bpy, a); 1,10-phenanthroline (phen, b); dipyridoquinoxaline (dpq, c) and dipyridophenazine (dppz, d) (Figure 1), were performed. These studies have been investigated by utilizing the electronic absorption spectroscopy, fluorescence spectra and ethidium bromide (EBr) displacement and gel filtration techniques. a-d complexes cooperatively bind and denature the DNA at low concentrations. Their concentration at midpoint of transition, L1/2, follows the order a >> b > c > d. Also the g, the number of binding sites per 1000 nucleotides, follows the order a >> b ~ c > d. EBr and Scatchard experiments for a-d complexes suggest efficient intercalative binding affinity to CT-DNA giving the order: d > c > b > a. Several binding and thermodynamic parameters are also described. The biological activity of these cationic and water soluble palladium complexes were tested against chronic myelogenous leukemia cell line, K562. b, c and d complexes show cytotoxic concentration (Cc50) values much lower than cisplatin.
PMCID: PMC4232794  PMID: 25587317
Pd(II) complexes; Cytotoxicity; DNA binding
11.  DNA Binding and Antitumor Activity of α-Diimineplatinum(II) and Palladium(II) Dithiocarbamate Complexes 
The two water-soluble designed platinum(II) complex, [Pt(Oct-dtc)(bpy)]NO3 (Oct-dtc = Octyldithiocarbamate and bpy = 2,2′ -bipyridine) and palladium(II) complex, [Pd(Oct-dtc)(bpy)]NO3, have been synthesized and characterized by elemental analyses, molar conductivity measurements, IR, 1H NMR, and electronic spectra studies. Studies of antitumor activity of these complexes against human cell tumor lines (K562) have been carried out. They show Ic50 values lower than that of cisplatin. The complexes have been investigated for their interaction with calf thymus DNA (CT-DNA) by utilizing the electronic absorption spectroscopy, fluorescence spectra, and ethidium bromide displacement and gel filtration techniques. Both of these water-soluble complexes bound cooperatively and intercalatively to the CT-DNA at very low concentrations. Several binding and thermodynamic parameters are also described.
doi:10.1155/2011/394506
PMCID: PMC3205611  PMID: 22110410
12.  Microwave synthesis of mixed ligand diimine–thiosemicarbazone complexes of ruthenium(ii): biophysical reactivity and cytotoxicity† 
A novel microwave-assisted synthetic method has been used to synthesise a series of mixed ligand ruthenium(ii) compounds containing diimine as well as bidentate thiosemicarbazone ligands. The compounds contain the diimine 1,10-phenanthroline (phen) or 2,2′-bipyridine (bpy) and the thiosemicarbazone is derived from 9-anthraldehyde. Based on elemental analyses and spectroscopic data, the compounds are best formulated as [(phen)2Ru(thiosemicarbazone)](PF6)2 and [(phen)2Ru(thiosemicarbazone)](PF6)2 where thiosemicarbazone = 9-anthraldehydethiosemicarbazone, 9-anthraldehyde-N(4)-methylthiosemicarbazone, and 9-anthraldehyde-N(4)-ethylthiosemicarbazone. Fluorescence competition studies with ethidium bromide, along with viscometric measurements suggests that the complexes bind calf thymus DNA (CTDNA) relatively strongly via an intercalative mode possibly involving the aromatic rings of the diimine ligands. The complexes show good cytotoxic profiles against MCF-7 and MDA-MB-231 (breast adenocarcinoma) as well as HCT 116 and HT-29 (colorectal carcinoma) cell lines.
doi:10.1039/b915081a
PMCID: PMC2814159  PMID: 20023905
13.  Multifaceted interplay between lipophilicity, protein interaction and luminescence parameters of non-intercalative ruthenium(II) polypyridyl complexes controlling cellular imaging and cytotoxic properties 
Here, we examine the photophysical properties of five ruthenium(II) complexes comprising two 4,7-diphenyl-1,10-phenanthroline (dip) ligands and functionalized bipyridine (R1bpy-R2, where R1 = H or CH3, R2 = H, CH3, COO−,4-[3-(2-nitro-1H-imidazol-1-yl)propyl] or 1,3-dicyclohexyl-1-carbonyl-urea) towards development of luminescence probes for cellular imaging. These complexes have been shown to interact with albumin and the formed adducts exhibited up to eightfold increase in the luminescence quantum yield as well as the average lifetime of emission. It was demonstrated that they cannot bind to DNA through the intercalation mode and its luminescence in the presence of DNA is quenching. Cell viability experiments indicated that all complexes possess significant dose-dependent cytotoxicity (with IC50 5–19 μM) on 4T1 breast cancer cell line and their anti-proliferative activity correlates very well with their lipophilicity. Cellular uptake was studied by measuring the ruthenium content in cells using ICP-MS technique. As expected, the better uptake is directly related to higher lipophilicity of doubly charged ruthenium complexes while uptake of monocationic one is much lower in spite of the highest lipophilicity. Additionally staining properties were assessed using flow cytometry and fluorescence microscopy. These experiments showed that complex with 1,3-dicyclohexyl-1-carbonyl-urea substituent exhibits the best staining properties in spite of the lowest luminescence quantum yield in buffered solution (pH 7.4). Our results point out that both the imaging and cytotoxic properties of the studied ruthenium complexes are strongly influence by the level of internalization and protein interaction.
Electronic supplementary material
The online version of this article (doi:10.1007/s00775-014-1187-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00775-014-1187-5
PMCID: PMC4240912  PMID: 25156150
Ruthenium polypyridyl complexes; Cytotoxicity; Optical imaging; Luminescence; Protein binding
14.  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
15.  Circular dichroism studies of ethidium bromide binding to the isolated nucleolus. 
Nucleic Acids Research  1976;3(8):1857-1873.
Circular dichroism in the 300-360 nm region and fluorescence induced by intercaltating binding of ethidum bromide to both DNA and RNA components were studied in isolated HeLa nucleoli. Both DNA and RNA compoents contribute to the induced dichroic elliticity. Digestion of nucleoli by RNase or DNase shows that most of the induced ellipticity comes from the DNA component. In nucleoli with an RNA/DNA = 0.8/1.0 the RNA component gives only 20% of the total ellipticity when measured at an ethidium bromide/DNA = 0.25. Spectro-fluorometric titration shows that ethidium bromide intercalates mostly into DNA in nucleoli. Both circular dichroism and fluorescence studies indicate that both DNA and RNA components in isolated nucleoli are less accessible to intercalating binding by ethidium bromide when compared to purified nucleolar DNA, DNA in chromatin or purified ribosomal RNA. Circular dichroic measurements of intercalating binding of ethidium bromide to to nucleoli may be used to study changes in nucleoli under different physiological or pathological conditions.
PMCID: PMC343045  PMID: 967680
16.  Zn2+ selectively stabilizes FdU-substituted DNA through a unique major groove binding motif 
Nucleic Acids Research  2011;39(10):4490-4498.
We report, based on semi-empirical calculations, that Zn2+ binds duplex DNA containing consecutive FdU–dA base pairs in the major groove with distorted trigonal bipyramidal geometry. In this previously uncharacterized binding motif, O4 and F5 on consecutive FdU are axial ligands while three water molecules complete the coordination sphere. NMR spectroscopy confirmed Zn2+ complexation occurred with maintenance of base pairing while a slight hypsochromic shift in circular dichroism (CD) spectra indicated moderate structural distortion relative to B-form DNA. Zn2+ complexation inhibited ethidium bromide (EtBr) intercalation and stabilized FdU-substituted duplex DNA (ΔTm > 15°C). Mg2+ neither inhibited EtBr complexation nor had as strong of a stabilizing effect. DNA sequences that did not contain consecutive FdU were not stabilized by Zn2+. A lipofectamine preparation of the Zn2+–DNA complex displayed enhanced cytotoxicity toward prostate cancer cells relative to the individual components prepared as lipofectamine complexes indicating the potential utility of Zn2+–DNA complexes for cancer treatment.
doi:10.1093/nar/gkr029
PMCID: PMC3105383  PMID: 21296761
17.  Cu(II), Ni(II), and Zn(II) Complexes of Salan-Type Ligand Containing Ester Groups: Synthesis, Characterization, Electrochemical Properties, and In Vitro Biological Activities 
A salen ligand on reduction and N-alkylation affords a novel [N2O2] chelating ligand containing ester groups [L = diethyl-2,2′-(propane-1,3-diylbis((2-hydroxy-3-methoxy benzyl)azanediyl))diacetate]. The purity of the ligand was confirmed by NMR and HPLC chromatograms. Its Cu(II), Ni(II), and Zn(II) complexes were synthesized and characterized by a combination of elemental analysis, IR, NMR, UV-Vis, and mass spectral data, and thermogravimetric analysis (TG/DTA). The magnetic moments, UV-Vis, and EPR spectral studies support square planar geometry around the Cu(II) and Ni(II) ions. A tetrahedral geometry is observed in four-coordinate zinc with bulky N-alkylated salan ligand. The redox properties of the copper complex were examined in DMSO by cyclic voltammetry. The voltammograms show quasireversible process. The interaction of metal complexes with CT DNA was investigated by UV-Vis absorption titration, ethidium bromide displacement assay, cyclic voltammetry methods, and agarose gel electrophoresis. The apparent binding constant values suggest moderate intercalative binding modes between the complexes and DNA. The in vitro antioxidant and antimicrobial potentials of the synthesized compounds were also determined.
doi:10.1155/2013/439848
PMCID: PMC3741936  PMID: 23983672
18.  Strong DNA deformation required for extremely slow DNA threading intercalation by a binuclear ruthenium complex 
Nucleic Acids Research  2014;42(18):11634-11641.
DNA intercalation by threading is expected to yield high affinity and slow dissociation, properties desirable for DNA-targeted therapeutics. To measure these properties, we utilize single molecule DNA stretching to quantify both the binding affinity and the force-dependent threading intercalation kinetics of the binuclear ruthenium complex Δ,Δ-[μ‐bidppz‐(phen)4Ru2]4+ (Δ,Δ-P). We measure the DNA elongation at a range of constant stretching forces using optical tweezers, allowing direct characterization of the intercalation kinetics as well as the amount intercalated at equilibrium. Higher forces exponentially facilitate the intercalative binding, leading to a profound decrease in the binding site size that results in one ligand intercalated at almost every DNA base stack. The zero force Δ,Δ-P intercalation Kd is 44 nM, 25-fold stronger than the analogous mono-nuclear ligand (Δ-P). The force-dependent kinetics analysis reveals a mechanism that requires DNA elongation of 0.33 nm for association, relaxation to an equilibrium elongation of 0.19 nm, and an additional elongation of 0.14 nm from the equilibrium state for dissociation. In cells, a molecule with binding properties similar to Δ,Δ-P may rapidly bind DNA destabilized by enzymes during replication or transcription, but upon enzyme dissociation it is predicted to remain intercalated for several hours, thereby interfering with essential biological processes.
doi:10.1093/nar/gku859
PMCID: PMC4191423  PMID: 25245944
19.  Interaction of Pyrrolobenzodiazepine (PBD) Ligands with Parallel Intermolecular G-Quadruplex Complex Using Spectroscopy and ESI-MS 
PLoS ONE  2012;7(4):e35920.
Studies on ligand interaction with quadruplex DNA, and their role in stabilizing the complex at concentration prevailing under physiological condition, has attained high interest. Electrospray ionization mass spectrometry (ESI-MS) and spectroscopic studies in solution were used to evaluate the interaction of PBD and TMPyP4 ligands, stoichiometry and selectivity to G-quadruplex DNA. Two synthetic ligands from PBD family, namely pyrene-linked pyrrolo[2,1-c][1,4]benzodiazepine hybrid (PBD1), mixed imine-amide pyrrolobenzodiazepine dimer (PBD2) and 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) were studied. G-rich single-stranded oligonucleotide d(5′GGGGTTGGGG3′) designated as d(T2G8), from the telomeric region of Tetrahymena Glaucoma, was considered for the interaction with ligands. ESI-MS and spectroscopic methods viz., circular dichroism (CD), UV-Visible, and fluorescence were employed to investigate the G-quadruplex structures formed by d(T2G8) sequence and its interaction with PBD and TMPyP4 ligands. From ESI-MS spectra, it is evident that the majority of quadruplexes exist as d(T2G8)2 and d(T2G8)4 forms possessing two to ten cations in the centre, thereby stabilizing the complex. CD band of PBD1 and PBD2 showed hypo and hyperchromicity, on interaction with quadruplex DNA, indicating unfolding and stabilization of quadruplex DNA complex, respectively. UV-Visible and fluorescence experiments suggest that PBD1 bind externally where as PBD2 intercalate moderately and bind externally to G-quadruplex DNA. Further, melting experiments using SYBR Green indicate that PBD1 unfolds and PBD2 stabilizes the G-quadruplex complex. ITC experiments using d(T2G8) quadruplex with PBD ligands reveal that PBD1 and PBD2 prefer external/loop binding and external/intercalative binding to quadruplex DNA, respectively. From experimental results it is clear that the interaction of PBD2 and TMPyP4 impart higher stability to the quadruplex complex.
doi:10.1371/journal.pone.0035920
PMCID: PMC3338766  PMID: 22558271
20.  Targeting the endoplasmic reticulum with a membrane-interactive luminescent ruthenium(ii) polypyridyl complex† †Electronic supplementary information (ESI) available: Experimental details, characterization of 2 and Fig. S1–S6. See DOI: 10.1039/c3sc51725j Click here for additional data file.  
Chemical Science  2013;4(12):4512-4519.
The characterization and bioactivity of the dinuclear ruthenium(ii) complex [(Ru(DIP)2)2(tpphz)]4+ (DIP = 4,7-diphenyl-1,10-phenanthroline and tpphz = tetrapyrido[3,2-a:2′,3′-c:3′′,2′′-h:2′′′,3′′′-j]phenazine) is reported.
The characterization and bioactivity of the dinuclear ruthenium(ii) complex [(Ru(DIP)2)2(tpphz)]4+ (DIP = 4,7-diphenyl-1,10-phenanthroline and tpphz = tetrapyrido[3,2-a:2′,3′-c:3′′,2′′-h:2′′′,3′′′-j]phenazine) is reported. This new complex is found to be luminescent in acetonitrile, where excitation into MLCT (metal-to-ligand charge-transfer) bands in the visible area of the spectrum (λ ex = 450 nm, ε = 45 000 M–1 cm–1) result in red emission (λ em,max = 620 nm, Φ MLCT = 0.017). Aqueous in vitro binding studies indicate that this complex binds to duplex DNA with an affinity of 1.8 × 106 M–1 through a non-classical groove-binding interaction, however, unlike the parent complex [(Ru(phen)2)2(tpphz)]4+ (phen = 1,10-phenanthroline), it also displays an increase in MLCT luminescence on addition of liposomes. Confocal microscopy and TEM studies show that this lipophilic complex targets the endoplasmic reticulum of eukaryotic cells, where it functions as an imaging agent for this organelle, and cytotoxicity studies in human cancer cell lines indicate a comparable potency to the anti-cancer drug cisplatin.
doi:10.1039/c3sc51725j
PMCID: PMC4285105  PMID: 25580209
21.  Synthesis and Characterization of the Ligand Based on Benzimidazole and Its Copper Complex: DNA Binding and Antioxidant Activity 
A new copper(II) complex with formulae of [Cu(buobb)2](pic)2, where buobb stands for the ligand of 1,3-bis(1- butylbenzimidazol-2-yl)-2-oxopropane and pic represents 2,4,6-trinitrophenol, has been synthesized and characterized by elemental analyses, molar conductivity, IR, UV-Vis spectra measurements, and cyclic voltammetry. The crystal structure of the copper(II) complex has been determined by X-ray single-crystal diffraction. The coordination environment around each copper(II) atom can be described as a distorted octahedral geometry. The π-π stacking interactions link the copper(II) complex into a 1D infinite network. The interactions of the ligand and the copper(II) complex with calf thymus DNA (CT-DNA) are investigated by using electronic absorption titration, ethidium bromide-DNA displacement experiments, and viscosity measurements. Additionally, the copper(II) complex's antioxidant properties have been investigated in vitro.
doi:10.1155/2011/105431
PMCID: PMC3226424  PMID: 22162669
22.  Cytotoxic Activities and DNA Binding Properties of 1-Methyl-7H-indeno[1,2-b]Quinolinium-7-(4-dimethylamino) Benzylidene Triflate 
DNA and Cell Biology  2012;31(6):1046-1053.
The interaction of calf thymus DNA (ct-DNA) with a novel synthesized pyrazolo[1,5-a]indole compound 1-methyl-7H-indeno[1,2-b]quinolinium-7-(4-dimethylamino) benzylidene triflate (MIDBT) was extensively studied by various spectroscopic techniques, viscosity measurements, and gel electrophoresis. The UV-visible observation implied that the compound interacted with ct-DNA by two binding modes, intercalating into the DNA base pairs and attaching to the helix exterior of DNA. The results of the fluorescent quenching and viscosity measurements showed that MIDBT could intercalate into DNA base pairs deeply in a classical intercalative mode. Circular dichroism results showed that the binding of MIDBT shifted ct-DNA conformation from B to A at low concentrations. In the gel electrophoresis, the compound was found to promote the cleavage of plasmid pBR 322 DNA effectively. Furthermore, cytotoxic studies of this compound against eleven selected tumor cell lines have been done. The values of 50% cytotoxic concentration (IC50) were in the range of 1.09–18.84 μM, exhibiting the potent cytotoxic properties.
doi:10.1089/dna.2011.1432
PMCID: PMC3378967  PMID: 22277048
23.  Differences in unwinding of supercoiled DNA induced by the two enantiomers of anti-benzo[a]pyrene diol epoxide. 
Nucleic Acids Research  1992;20(23):6167-6176.
The unwinding of supercoiled phi X174 RFI DNA induced by the tumorigenic (+) and non-tumorigenic (-) enantiomers of trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) has been investigated by agarose slab-gel and ethidium titration tube gel electrophoresis. The differences in adduct conformations were verified by flow linear dichroism techniques. Both enantiomers cause a reversible unwinding by the formation of noncovalent intercalative complexes. The effects of covalently bound BPDE residues on the electrophoretic mobilities of the RF I DNA form in agarose gels were investigated in detail in the range of binding ratios rb approximately 0.0-0.06 (covalently bound BPDE residues/nucleotide). In this range of rb values, there is a striking difference in the mobilities of (+)-BPDE- and (-)-BPDE-adducted phi X174 DNA in agarose slab-gels, the covalently bound (+)-BPDE residues causing a significantly greater retardation than (-)-BPDE residues. Increasing the level of covalent adducts beyond rb approximately 0.06 in the case of the (+)-BPDE enantiomer, leads to further unwinding and a minimum in the mobilities (corresponding to comigration of the nicked form and the covalently closed relaxed modified form) at rb 0.10 +/- 0.01; at still higher rb values, rewinding of the modified DNA in the opposite sense is observed. From the minimum in the mobility, a mean unwinding angle (per BPDE residue) of theta = 12 +/- 1.5 degrees is determined, which is in good agreement the value of theta = 11 +/- 1.8 degrees obtained by the tube gel titration method. Using this latter method, values of theta = 6.8 +/- 1.7 degrees for (-)-BPDE-phi X174 adducts are observed. It is concluded that agarose slab gel techniques are not suitable for determining unwinding angles for (-)-BPDE-modified phi X174 DNA because the alterations in the tertiary structures for rb < 0.06 are too small to cause sufficiently large changes in the electrophoretic mobilities. The major trans (+)-BPDE-N2-guanosine covalent adduct is situated at external binding sites and the mechanisms of unwinding are therefore different from those relevant to noncovalent intercalative BPDE-DNA complexes or to classical intercalating drug molecules; a flexible hinge joint and a widening of the minor groove at the site of the lesion may account for the observed unwinding effects. The more heterogeneous (-)-BPDE-nucleoside adducts (involving cis and trans N2-guanosine, and adenosine adducts) are less effective in causing unwinding of supercoiled DNA for reasons which remain to be elucidated.
Images
PMCID: PMC334500  PMID: 1475180
24.  Unusually Strong Binding to the DNA Minor Groove by a Highly Twisted Benzimidazole-Diphenylether: Induced Fit and Bound Water† 
Biochemistry  2007;46(23):6944-6956.
RT29 is a dicationic diamidine derivative that does not obey the classical “rules” for shape and functional group placement that are expected to result in strong binding and specific recognition of the DNA minor groove. The compound contains a benzimidazole-diphenyl ether core that is flanked by the amidine cations. The diphenyl ether is highly twisted and gives the entire compound too much curvature to fit well to the shape of the minor groove. DNaseI footprinting, fluorescence intercalator displacement studies and circular dichroism spectra, however, indicate that the compound is an AT specific minor groove binding agent. Even more surprisingly, quantitative biosensor-surface plasmon resonance and isothermal titration calorimetric results indicate that the compound binds with exceptional strength to certain AT sequences in DNA with a large negative enthalpy of binding. Crystallographic results for the DNA complex of RT29 compared to calculated results for the free compound show that the compound undergoes significant conformational changes to enhance its minor groove interactions. In addition, a water molecule is incorporated directly into the complex to complete the compound-DNA interface and it forms an essential link between the compound and base pair edges at the floor of the minor groove. The calculated ΔCp value for complex formation is substantially less than the experimentally observed value in support of water being an intrinsic part of the complex with a major contribution to the ΔCp value. Both the induced fit conformational changes of the compound and the bound water are essential for strong binding to DNA by RT29.
doi:10.1021/bi700288g
PMCID: PMC2519038  PMID: 17506529
25.  Sequence Specific Binding of Beta Carboline Alkaloid Harmalol with Deoxyribonucleotides: Binding Heterogeneity, Conformational, Thermodynamic and Cytotoxic Aspects 
PLoS ONE  2014;9(9):e108022.
Background
Base dependent binding of the cytotoxic alkaloid harmalol to four synthetic polynucleotides, poly(dA).poly(dT), poly(dA-dT).poly(dA-dT), poly(dG).poly(dC) and poly(dG-dC).poly(dG-dC) was examined by various photophysical and calorimetric studies, and molecular docking.
Methodology/Principal Findings
Binding data obtained from absorbance according to neighbor exclusion model indicated that the binding constant decreased in the order poly(dG-dC).poly(dG-dC)>poly(dA-dT).poly(dA-dT)>poly(dA).poly(dT)>poly(dG).poly(dC). The same trend was shown by the competition dialysis, change in fluorescence steady state intensity, stabilization against thermal denaturation, increase in the specific viscosity and perturbations in circular dichroism spectra. Among the polynucleotides, poly(dA).poly(dT) and poly(dG).poly(dC) showed positive cooperativity where as poly(dG-dC).poly(dG-dC) and poly(dA-dT).poly(dA-dT) showed non cooperative binding. Isothermal calorimetric data on the other hand showed enthalpy driven exothermic binding with a hydrophobic contribution to the binding Gibbs energy with poly(dG-dC).poly(dG-dC), and poly(dA-dT).poly(dA-dT) where as harmalol with poly(dA).poly(dT) showed entropy driven endothermic binding and with poly(dG).poly(dC) it was reported to be entropy driven exothermic binding. The study also tested the in vitro chemotherapeutic potential of harmalol in HeLa, MDA-MB-231, A549, and HepG2 cell line by MTT assay.
Conclusions/Significance
Studies unequivocally established that harmalol binds strongly with hetero GC polymer by mechanism of intercalation where the alkaloid resists complete overlap to the DNA base pairs inside the intercalation cavity and showed maximum cytotoxicity on HepG2 with IC50 value of 14 µM. The results contribute to the understanding of binding, specificity, energetic, cytotoxicity and docking of harmalol-DNA complexation that will guide synthetic efforts of medicinal chemists for developing better therapeutic agents.
doi:10.1371/journal.pone.0108022
PMCID: PMC4172587  PMID: 25247695

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