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PubMed1995

Solution structure of a DNA complex with the fluorescent bis-intercalator TOTO determined by NMR spectroscopy.

We have used two-dimensional 1H NMR spectroscopy to determine the solution structure of the DNA oligonucleotide d(5'-CGCTAGCG-3')2 complexed with the bis-intercalating dye 1,1'-(4,4,8,8-tetramethyl-4,8-diazaundecamethylene)bis[4-(3-methyl -2,3- dihydrobenzo-1,3-thiazolyl-2-methylidene)qui nolinium] tetraiodide (TOTO). The determination of the structure was based on total relaxation matrix analysis of the NOESY cross-peak intensities using the program MARDIGRAS. Improved procedures to consider the experimental "noise" in NOESY spectra during these calculations have been employed. The NOE-derived distance restraints were applied in restrained molecular dynamics calculations. Twenty final structures each were generated for the TOTO complex from both A-form and B-form dsDNA starting structures. The root-mean-square (rms) deviation of the coordinates for the 40 structures of the complex was 1.45 A. The local DNA structure is distorted in the complex. The helix is unwound by 60 degrees and has an overall helical repeat of 12 base pairs, caused by bis-intercalation of TOTO. The poly(propylenamine) linker chain is located in the minor groove of dsDNA. Calculations indicate that the benzothiazole ring system is twisted relative to the quinoline in the uncomplexed TOTO molecule. The site selectivity of TOTO for the CTAG-CTAG site is explained by its ability to adapt to the base pair propeller twist of dsDNA to optimize stacking and the hydrophobic interaction between the thymidine methyl group and the benzothiazole ring. There is a 3000-fold fluorescence enhancement upon binding of TOTO to dsDNA. Rotation about the cyanine methine bonds is possible in free TOTO, allowing relaxation nonradiatively. When bound to dsDNA, the benzothiazole ring and the quinolinium ring are clamped by the nucleobases preventing this rotation, and the chromophore loses excitation energy by fluorescence instead.

Base Composition↗
PubMed1993

Minor groove binding of SN6999 to an alkylated DNA: molecular structure of d(CGC[e6G]AATTCGCG)-SN6999 complex.

The interaction between a potent synthetic antitumor and antiviral minor groove binding drug 1-methyl-4-[4-[4-(4-(1-methylquinolinium)amino)benzamido]anilino] pyridinium dichloride (SN6999) and an alkylated DNA d(CGC[e6G]AATTCGCG) dodecamer has been studied by X-ray crystallography. The complex forms a new crystal lattice in the space group P2(1)2(1)2(1) with unit cell dimensions of a = 28.48 A, b = 36.11 A, and c = 69.60 A. The structure has been solved by the molecular replacement method and refined to an R-factor of 17.0% at approximately 2.5 A resolution using 1618 reflections. In the complex, the SN6999 covers almost six base pairs in the narrow minor groove with the 1-methylquinolinium (Q) ring near T8-A17 and the 1-methylpyridinium (P) ring near the C3-G22 base pair. The central benzamido (BQ) and anilino (BP) rings are essentially coplanar, with the Q and P rings having large dihedral angles of 38 degrees and 39 degrees, respectively, to the plane of BQ/BP. There is only one direct hydrogen bond between the amide NH of SN6999 to T20O2 of DNA. The drug-DNA interaction is stabilized by stacking interaction of sugar oxygens from T20O4' to BQ and C21O4' to BP. There is charge-induced dipole interaction between the positively charged nitrogen atom of 1-methylquinolinium with C9O4' and that of 1-methylpyridinium with G22O4'. The crystal structure of the complex can be used to explain the NMR results. SN6999 lacks the crescent shape observed in other minor groove binding drugs and distorts the DNA duplex upon binding. The complex packs in the lattice using the G-N2:G-N3 interlocking base pairs at both ends of the helix. As in earlier cases, the two independent e6G:C base pairs adopt different base pairing schemes. The e6G16:C9 base pair adopts a previously observed bifurcated configuration involving three-centered hydrogen bonds and is similar to a Watson-Crick pairing. In contrast, the e6G4:C21 base pair adopts a novel "reverse wobble" configuration with C21 being pushed toward the major groove side. The ethyl group is in the proximal orientation (to N7) in both base pairs. Taken together with the observations found in the same DNA complexed to Hoechst 33258, Hoechst 33342, and retropsin from different crystal lattices, the results suggest that the e6G:C base pairing is weak and polymorphic when compared to a normal G:C base pair and the DNA duplex containing this lesion is readily distorted.

Alkylation↗
PubMed1992

Two-dimensional NMR studies of d(GGTTAATGCGGT).d(ACCGCATTAACC) complexed with the minor groove binding drug SN-6999.

The dodecadeoxynucleotide duplex d(GGTTAATGCGGT).d(ACCGCATTAACC) and its 1:1 complex with the minor groove binding drug SN-6999 have been prepared and studied by two-dimensional 1H nuclear magnetic resonance spectroscopy. Complete sequence-specific assignments have been obtained for the free duplex by standard methods. The line widths of the resonances in the complex are greater than those observed for the free duplex, which complicates the assignment process. Extensive use of two-quantum spectroscopy was required to determine the scalar correlations for identifying all of the base proton and most of the 1'H-2'H-2''H spin subsystems for the complex. This permitted unambiguous sequence-specific resonance assignments for the complex, which provides the necessary background for a detailed comparison of the structure of the duplex, with and without bound drug. A series of intermolecular NOEs between drug and DNA were identified, providing sufficient structural constraints to position the drug in the minor groove of the duplex. However, the combination of NOEs observed can only be rationalized by a model wherein the drug binds in the minor groove of the DNA in both orientations relative to the long helix axis and exchanges rapidly between the two orientations. The drug binds primarily in the segment of five consecutive dA-dT base pairs d(T3T4A5A6T7).d(A18T19T20A21A22), but surprisingly strong interactions are found to extend one residue in the 3' direction along each strand to G8 and C23. The observation of intermolecular contacts to residues neighboring the AT-rich region demonstrates that the stabilization of the bis(quaternary ammonium) heterocycle family of AT-specific, minor groove binding drugs is not based exclusively on interactions with dA-dT base pairs.

Antineoplastic Agents↗
PubMed1994

Reconstitution of purified GABAA receptors: ligand binding and chloride transporting properties.

GABAA receptors have been solubilized from bovine brain membranes and, following purification by benzodiazepine affinity chromatography, have been reconstituted into phospholipid vesicles. Reconstituted vesicles were about 120 nm in diameter, and, on average, each vesicle contained fewer than one GABAA receptor which was reconstituted in an outside-out orientation. These preparations have been used in parallel studies of radiolabeled ligand binding and chloride flux, the latter being measured by following the fluorescence changes of a chloride-sensitive probe which was trapped within the vesicles at the time of reconstitution. The benzodiazepine [3H]flunitrazepam binds to an apparently homogeneous population of sites in these preparations (Kd of 5 nM) whereas the GABA analogue [3H]muscimol binds to both high- and low-affinity sites (KdS of 10 nM and 0.27 microM). Muscimol stimulated chloride flux with an EC50 of 0.2 microM and, at similar concentrations (EC50 = 0.16 microM), potentiated [3H]flunitrazepam binding, suggesting that occupancy of the low-affinity sites may be important for these effects. Diazepam shifted the dose-response curve for muscimol-stimulated flux to about 4-fold lower concentrations without affecting the maximum response. Diazepam did not, however, alter the equilibrium binding of [3H]muscimol. The purified receptor showed densensitization since flux responses were abolished by prior exposure to muscimol. The competitive antagonist bicuculline and the channel blocker picrotoxin completely inhibited ion flux mediated by 3 microM muscimol with EC50 values of 5.3 and 2.5 microM, respectively. These results are discussed in terms of possible mechanisms for activation, inhibition, and modulation of GABAA receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Membrane chloride transport measured using a chloride-sensitive fluorescent probe.

Transport of chloride across cell membranes through exchange, cotransport, or conductive pathways is a subject of great biological importance. Current methods of measurement are restricted in their sensitivity, time resolution, and applicability. A new transport measurement technique has been developed on the basis of the fluorescence quenching by chloride of the dye 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ). SPQ fluorescence quenching by chloride is rapid (less than 1 ms) and sensitive, with a greater than 50% decrease in fluorescence at 10 mM chloride. SPQ fluorescence is not altered by other physiological anions or by pH and can be used to measure both neutral and conductive transport processes. The high water solubility and membrane permeability properties of SPQ make it ideal for use in both membrane vesicles and cells. Chloride transport determined with SPQ was validated by measurement of erythrocyte chloride/anion exchange and membrane vesicle chloride conductance.

Biological Transport↗
PubMed1988

Sodium-dependent chloride transport in basolateral membrane vesicles isolated from rabbit proximal tubule.

The mechanisms for Cl transport across basolateral membrane vesicles (BLMV) isolated from rabbit renal cortex were examined by using the Cl-sensitive fluorescent indicator 6-methoxy-N-(3-sulfopropyl)quinolinium (SPQ). The transporters studied included Cl/base exchange, Cl/base/Na cotransport, K/Cl cotransport, and Cl conductance. Initial rates of chloride influx (JCl) were determined from the measured time course of SPQ fluorescence in BLMV following inwardly directed gradients of Cl and gradients of other ions and/or pH. For a 50 mM inwardly directed Cl gradient in BLMV which were voltage and pH clamped (7.0) using K/valinomycin and nigericin, JCl was 0.80 +/- 0.14 nmol S-1 (mg of vesicle protein)-1 (mean +/- SD, n = 8 separate preparations). In the absence of Na and CO2/HCO3 in voltage-clamped BLMV, JCl increased 56% +/- 5% in response to a 1.9 pH unit inwardly directed H gradient; the increase was further enhanced by 40% +/- 3% in the presence of CO2/HCO3 and inhibited 30% +/- 8% by 100 microM dihydro-4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. Na gradients did not increase JCl in the absence of CO2/HCO3; however, an outwardly directed Na gradient in the presence of CO2/HCO3 increased JCl by 31% +/- 8% with a Na KD of 7 +/- 2 mM. These results indicate the presence of Cl/OH and Cl/HCO3 exchange, and Cl/HCO3 exchange trans-stimulated by Na. There was no significant effect of K gradients in the presence or absence of valinomycin, suggesting lack of significant K/Cl cotransport and Cl conductance under experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Interactions of the dimethyldiazaperopyrenium dication with nucleic acids. 1. Binding to nucleic acid components and to single-stranded polynucleotides and photocleavage of single-stranded oligonucleotides.

The binding of dimethyldiazaperopyrenium dication (1) with nucleosides, nucleotides, and single-stranded polynucleotides has been studied by photophysical methods. It has been shown that 1 may be a potential selective fluorescent probe for A- and/or T-rich polynucleotides. 1 efficiently cleaves oligonucleotides at guanine sites, under illumination with visible light, and therefore may be used as a sequence-specific artificial photonuclease.

Base Sequence↗
PubMed1989

Interactions of the dimethyldiazaperopyrenium dication with nucleic acids. 2. Binding to double-stranded polynucleotides.

The interactions of dimethyldiazaperopyrenium dication (1) with DNA have been studied by spectroscopic methods: absorption, static and dynamic fluorescence, and linear dichroism. 1 binds strongly to DNA at 250 mM NaCl, with a higher affinity for G-C pairs as compared to A-T pairs. The dye fluorescence is enhanced when it is bound to A-T pairs, whereas the emission is quenched in the vicinity of G-C pairs. Evidence for intercalation has been obtained via energy transfer and linear dichroism measurements.

Base Composition↗
PubMed1989

Quantitative fluorescence measurement of chloride transport mechanisms in phospholipid vesicles.

A quantitative fluorescence assay has been developed to measure Cl flux across liposomal membranes for use in chloride transporter reconstitution studies. A Cl-sensitive fluorophore [6-methoxy-N-(3-sulfopropyl)quinolinium; SPQ] was entrapped into phospholipid/cholesterol liposomes formed by bath sonication, high-pressure extrusion, and detergent dialysis. Liposomes containing entrapped SPQ were separated from external SPQ by passage down a Sephadex G25 column. There was less than 10% leakage of SPQ from liposomes in 8 h at 4 degrees C and in 2 h at 23 degrees C. Cl influx (JCl in millimolar per second or nanomoles per second per centimeter squared) was determined from the time course of SPQ fluorescence, measured by cuvette or stopped-flow fluorometry, in response to inward Cl gradients. In 90% phosphatidylcholine (10% cholesterol liposomes at 23 degrees C, JCl in response to a 50 mM inward Cl gradient was 0.06 +/- 0.01 mM.s-1 (SD, n = 3) in the absence and 0.27 +/- 0.02 mM.s-1 in the presence of a K/valinomycin voltage clamp (0 mV), showing that the basal Cl "leak" is conductive; JCl increased (1.7 +/- 0.1)-fold in the presence of a 60-mV inside-positive diffusion potential. Accuracy of chloride influx rates determined by the SPQ method was confirmed by measurement of 36Cl uptake. In liposomes voltage-clamped to 0 mV, JCl was linear with external [Cl] (0-100 mM), independent of pH gradients, and strongly dependent on temperature (activation energy 18 +/- 1 kcal/mol, 12-42 degrees C) as predicted for channel-independent Cl diffusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport, Active↗
PubMed1998

Dynamics of a bis-intercalator DNA complex by 1H-detected natural abundance 13C NMR spectroscopy.

The dynamics of the DNA oligomer d(CGCTAGCG)2 (CTSYM) and its complex with the dye 1,1-(4,4,8,8-tetramethyl-4, 8-diazaundecamethylene)-bis-4-(3-methyl-2,3-dihydro-(benzo-1, 3-thiazole)-2-methylidene)-quinolinium tetraiodide (TOTO) (CTSYMTOTO) bis-intercalated at the 5'-CT-3' sequence steps have been determined from NMR relaxation parameters. Longitudinal and transverse 13C relaxation rates and heteronuclear NOE relaxation data were acquired and have been analyzed in the context of the Lipari and Szabo model-free formalism. The overall rotational correlation time for the CTSYM is 3.44 ns and the CTSYMTOTO is 3.48 ns. The generalized order parameters (S2) for methine carbons in the CTSYM and CTSYMTOTO are relatively high but nonuniform for the molecules and show sequence context and conformation-dependent variations. Average values of S2 = 0.79 +/- 0.02 for the CTSYM, S2 = 0.80 +/- 0.04 for the CTSYMTOTO aromatic spins, S2 = 0.76 +/- 0.02 for the CTSYM, and S2 = 0.83 +/- 0.05 for the CTSYMTOTO deoxyribose spins were found. The S2 values for the 5'-terminal deoxyribose are lower than for the other residues. The DNA backbone in CTSYMTOTO is distorted and elongated at the site of intercalation, and the C3' atom of the C3 deoxyribose residue has a very low S2 = 0.57 +/- 0.06. The low order for this spin is interpreted in terms of exchange between the C2'-endo and O1'-endo conformations of the C3 deoxyribose. Significant chemical exchange processes were found for most of the aromatic spins in CTSYM that are interpreted in terms of microsecond to millisecond time scale dynamics. The microsecond to millisecond dynamics of the bases in CTSYM are quenched upon TOTO complex formation due to unwinding of the helix and an increase in the surface area of the bases in mutual contact and the large surface area in contact with the intercalated dye. The derived order parameters combined with the solution structure provide motional models for conformational changes induced in the backbone in response to the ligand binding.

DNA↗
PubMedDate not supplied

DNA length evaluation using cyanine dye and fluorescence correlation spectroscopy.

To develop a high-performance method for measuring the length of double-stranded DNA (dsDNA) fragments, the capability of fluorescence correlation spectroscopy (FCS) was examined. To omit troublesome and time-consuming labeling operations such as PCR with fluorescently labeled mononucleotides or primers, intercalation of dimeric cyanine dye YOYO-1 iodide (YOYO) to dsDNA was utilized as a simple labeling method. Various lengths of dsDNA fragments were prepared and mixed with YOYO prior to FCS, and the dependence of the diffusion time of a dsDNA-YOYO complex on the length of dsDNA fragment and the dsDNA/YOYO ratio was investigated. It was successfully demonstrated that the dsDNA length can be measured using YOYO and FCS, and the calibration curve was developed taking into account the rewinding and expansion of the dsDNA fragment caused by YOYO intercalation.

Benzoxazoles↗
PubMed2001

Photobleaching of asymmetric cyanines used for fluorescence imaging of single DNA molecules.

The photobleaching of the cyanine dyes YO and YOYO has been investigated for both free and DNA-bound dyes, using absorption and fluorescence spectroscopy coupled with fluorescence microscopy. For the free dyes, the nature of the reactive species involved in the photodegradation process is different for the monomer and the dimer, as shown by scavenger studies. For DNA-bound dyes, photoinduced fading of the visible absorption band occurs by different pathways depending on the drug binding mode and can be attenuated by appropriate scavengers. However, none of these scavengers were found to have any significant effect on the photobleaching of dye fluorescence. It appears that the reduction of fluorescence intensity comes from a quenching of the dye fluorescence by modified DNA bases, possibly 8-oxo-7,8-dihydro-2'-deoxyguanosine.

Animals↗
PubMed2002

Chemical properties of a para-benzyne.

5,8-Didehydroisoquinolinium ion, a para benzyne analogue, was generated in a Fourier transform ion cyclotron resonance mass spectrometer, and its reactivity toward various neutral reagents was examined. A direct comparison of the reaction kinetics of the para benzyne, a meta isomer, and analogous monoradicals, indicates that the para benzyne is a poorer electrophile but a more reactive radical than its meta isomer.

Free Radicals↗
PubMed2003

Micelle-sequestered dissociation of cationic DNA-intercalated drugs: unexpected surfactant-induced rate enhancement.

Detergent sequestration using micelles as a hydrophobic sink for dissociated drug molecules is an established technique for determination of dissociation rates. The anionic surfactant molecules are generally assumed not to interact with the anionic DNA and thereby not to affect the rate of dissociation. By contrast, we here demonstrate that the surfactant molecules sodium dodecyl sulfate (SDS), sodium decyl sulfate, and sodium octyl sulfate all induce substantial rate enhancements of the dissociation of intercalators from DNA. Four different cationic DNA intercalators are studied with respect to surfactant-induced dissociation. Except for the smallest intercalator, ethidium, the dissociation rate constants increase monotonically with surfactant concentration both below cmc and (more strongly) above cmc, much more than expected from electrostatic effects of increased counterion concentration. The rate enhancement, most pronounced for the bulky, multicationic, hydrophobic DNA ligands in this study, indicates a reduction of the activation energy for the ligand to pass out from a deeply penetrating intercalation site of DNA. The discovery that surfactants enhance the rate of dissociation of cationic DNA-intercalators implies that rate constants previously determined by micelle-sequestered dissociation may have been overestimated. As an alternative, more reliable method, we suggest instead the addition of excess of dummy DNA as an absorbent for dissociated ligand.

Benzoxazoles↗
PubMed2004

Selective catalysis with peptide dendrimers.

Peptide dendrimers incorporating 3,5-diaminobenzoic acid 1 as a branching unit (B) were prepared by solid-phase synthesis of ((Ac-A(3))(2)B-A(2))(2)B-Cys-A(1)-NH(2) followed by disulfide bridge formation. Twenty-one homo- and heterodimeric dendrimers were obtained by permutations of aspartate, histidine, and serine at positions A(1), A(2), and A(3). Two dendrimers catalyzed the hydrolysis of 7-hydroxy-N-methyl-quinolinium esters (2-5), and two other dendrimers catalyzed the hydrolysis of 8-hydroxy-pyrene-1,3,6-trisulfonate esters (10-12). Enzyme-like kinetics was observed in aqueous buffer pH 6.0 with multiple turnover, substrate binding (K(M) = 0.1-0.5 mM), rate acceleration (k(cat)/k(uncat) > 10(3)), and chiral discrimination (E = 2.8 for 2-phenylpropionate ester 5). The role of individual amino acids in catalysis was investigated by amino acid exchanges, highlighting the key role of histidine as a catalytic residue, and the importance of electrostatic and hydrophobic interactions in modulating substrate binding. These experiments demonstrate for the first time selective catalysis in peptide dendrimers.

Amino Acids↗
PubMed2005

Reactivity of the N-methylene-5,8-didehydroisoquinolinium triradical ion.

The reactivity of a sigma,sigma,pi-triradical, N-methylene-5,8-didehydroisoquinolinium ion, has been compared to that of four related mono- and biradicals in a Fourier transform ion cyclotron resonance mass spectrometer. The triradical contains two weakly interacting orthogonal radical systems-the sigma,sigma-biradical moiety and the pi-monoradical moiety. The sigma,sigma-biradical moiety is found to be substantially more reactive than the pi-radical moiety. The pi-radical site reacts only after reactions have quenched the sigma-radical sites.

Free Radicals↗
PubMed2005

Amine capture strategy for peptide bond formation by means of quinolinium thioester salts.

A new and unprecedented exploitation of quinolinium thioester salts 2 in peptide bond formation is reported. These synthetic tools were assessed during the preparation of a number of dipeptides 3a-f obtained in good yields with complete stereochemical integrity. A sequential mechanism related to a prior amine capture strategy is well-established. Additionally, a tripeptide 3g was prepared according to a "safety-catch" approach, thus demonstrating the important potential of these new synthetic tools in the design of new safety-catch linkers exploitable in Solid-Phase Peptide Synthesis (SPPS).

Amines↗