Einar Sletten

Intramolecular DNA coiling mediated by metallo-supramolecular cylinders: Differential binding of P and M helical enantiomers

We have designed a synthetic tetracationic metallo-supramolecular cylinder that targets the major groove of DNA with a binding constant in excess of 107 M−1 and induces DNA bending and intramolecular coiling. The two enantiomers of the helical molecule bind differently to DNA and have different structural effects. We report the characterization of the interactions by a range of biophysical techniques. The M helical cylinder binds to the major groove and induces dramatic intramolecular coiling. The DNA bending is less dramatic for the P enantiomer.

Interaction between ciprofloxacin and DNA mediated by Mg2+-ions

Abstract The oligonucleotide duplex d(C1C2T3C4G5C6T7C8T9C10)·d(G11A12G13A14G15C16G17A18G19G20) has been titrated with the fluoroquinolone ciprofloxacin (CFX) using 1H 1D and 2D NMR spectroscopy to monitor the interaction pattern. The assignments of key intermolecular proton–proton crosspeaks in the NOESY map between the fluoroquinolone and the duplex prove the existence of predominantly minor groove CFX–duplex interactions. When MgCl2 was added to a solution of 1:1 CFX–duplex until a final concentration of Mg2+–[PO4]=1, the binding pattern did not change significantly. Theoretical calculations (Docking) carried out on a model of the ternary CFX–Mg2+–duplex adduct using a key interproton distance derived from the NOESY map as anchoring, produced an energetically favourable orientation of the CFX–Mg2+ in the minor groove.

A novel type of bidentate purinemetal bonding. Catena-tetraaquo-μ-purine-copper(II) sulphate dihydrate

Abstract [Cu(C5H4N4)(H2O)4]SO4·2H2O, orthorhombic, space group Pbca, a = 11.912(5) A, b = 17.828(2) A, c = 12.673(2) A, Z = 8. The data were collected on a CAD-4 diffractometer using an on-line PDP 11/55 computer for structure analysis. The structure was refined to R = 0.119. The Cu ion is octahedrally surrounded, binding equatorially to N(7) and N(9) in two symmetry related purine rings, thus producing a polymeric chain. The other positions are occupied by water molecules. The CuN(9) distance (2.036 A) is in the range expected for a dative bond while the CuN(7) distance (1.903 A) is close to the value expected for a covalent bond. The purine ligand is neutral being protonated at N(1). The sulphate group is disordered and there is a large degree of pseudo-symmetry in the structure.

Multivariate calibration of diffuse reflectance infrared spectra of coals as an alternative to rank determination by vitrinite reflectance

Abstract Christy, A.A., Velapoldi, R.A., Karstang, T.V., Kvalheim, O.M., Sletten, E. and Telnaes, N., 1987. Multivariate calibration of diffuse reflectance infrared spectra of coals as an alternative to rank determination by vitrinite reflectance. Chemometrics and Intelligent Laboratory Systems , 2:199-207. Sixty-four randomly selected, vitrinite-rich coal samples were subjected to petrological, spectrometric and multivariate data analysis. Diffuse reflectance Fourier transform infrared spectra in a Kubelka-Munk format were reduced by a maximum entropy reduction method and were calibrated against vitrinite reflectance using partial least squares regression. Two calibration models were calculated. One model was calculated for coal samples with vitrinite reflectance from 0.38 to 1.08, i.e., including most of the maturity range defined as the “oil window”. Outliers or non-population members were identified by an iterative process, leaving a total of 41 coal samples. The cross-validated model gave an absolute prediction error of ± 0.09, a value of the same order of magnitude as the average standard deviation of the vitrinite reflectance measurements (1 s = 0.06). The second model was calculated for eighteen samples with maturity from 1.32 to 3.54. An absolute prediction error of ±0.15 was obtained, reflecting the higher uncertainty in the vitrinite reflectance measurements for the higher-ranking coals.

Methionine Can Favor DNA Platination by trans‐Coordinated Platinum Antitumor Drugs

Cisplatin (cis-DDP) and its cis-coordinated analogues, carboplatin and oxaliplatin, have been successfully used in the treatment of testicular and other solid tumors, but applications are restricted by side effects and intrinsic and acquired resistances. The discovery of trans-coordinated platinum complexes with antitumor activity provides a novel approach for cancer chemotherapy. Among several types of transplatinum complexes, trans-[PtCl2{E-HN=C(OCH3)CH3}2] (trans-EE) raised particular interest because of its higher cytotoxicity than the cis isomer and its activity towards several cis-DDP-resistant tumor cells. Mechanistic studies indicated that trans-EE has different DNA binding modes relative to cis-DDP, although their reaction rates were similar. DNAmodified by trans-EE could not be recognized by high-mobility group (HMG), the protein that interferes with DNA repair of cis-DDP adducts, whereas histone H1 could bind to trans-EE-modified DNA and prevent DNA polymerization and repair. A recent study also indicated that methionine was the preferable binding site of trans-EE in the reaction with cytochrome c, and different binding modes were observed between cisand trans-platinum complexes. Many cellular molecules, including proteins, peptides, and also some small molecules, can play significant roles in the functioning of and resistance to drugs, such as DNA platination, drug transport, and efflux. Sulfur-containing proteins are of special interest because of their high affinity for platinum, their abundance (e.g. albumin), and their involvement in metal-ion transport (e.g. the copper transporter protein CTR1, which contains methionine-rich extracellular motifs and appears to be involved in platinum-drug transport through the cell membrane). Kinetic studies indicated that the S platination of l-methionine (Met) or Nacetyl-l-methionine (AcMet) was kinetically preferred, whereas N7 coordination of guanine was thermodynamically favored. Studies using the model compound [PtCl(dien)] showed that the migration of platinum from S-Met to N7guanine (G–N7) was fairly slow (t1/2= 21–147 h at 310 K depending on DNA sequence), which was obviously slower than the direct DNA platination by [PtCl(dien)]. Although Met could slightly increase the rate of platination of cis-DDP to guanosine monophosphate (GMP), the reaction with synthetic DNA showed that the presence of Met actually inhibited platination on both single strand (ss) and double strand (ds) DNA. Herein we show that the platination rates of both GMP and DNA are substantially enhanced by a Met ligand bound to trans-EE. Moreover the reaction is highly pH-dependent. This enhancement has been observed for all nucleotides used in this work, including monomeric GMP, synthetic ssand dsDNA, and natural DNA. It has been observed that the formation of a Met intermediate is about seven times faster than G–N7 platination (Figure S1 in the Supporting Information). Accordingly, DNA platination is significantly faster via a Met intermediate (Scheme 1). On the basis of activity studies and the formation of this type of adducts also in the cellular system, it is suggested that the mechanism of trans-EE could differ substantially from that of conventional cisplatinum compounds.

Prediction of physical properties of hydrocarbon mixtures by partial-least-squares calibration of carbon-13 nuclear magnetic resonance data

By using the partial-least-squares (PLS) method, bulk properties of 12-component synthetic mixtures containing n-alkanes, iso-alkanes, cyclo-alkanes and aromatics are calibrated against intensities and chemical shifts of 13C-NMR spectra. The standard error of prediction (SEP) for the determinations of density, refractive index, mean molecular weight and carbon-type distribution was found to be less than 3.2% of the observed range. The SEP for excess densities is significantly larger, especially for values based on chemical shift data. The chemical shift variation supplies unique chemical information on solute/solvent interactions.

NMR Spectroscopy of Anticancer Platinum Drugs

The focus of this review is on recently published papers (2000-2005) where NMR spectroscopy has been applied as the principal method in the study of anticancer platinum drugs. The paper gives an overview of the basic NMR techniques particularly relevant for studying interaction between platinum compounds and nucleic acid constituents. The latest NMR studies on the well-known anticancer drug cisplatin, with focus on kinetics and cisplatin-DNA structures are reported. Also cisplatin analogues clinically approved or currently in clinical trials are discussed. In addition two new classes of anticancer platinum drugs are described: trans-oriented Pt iminoether complexes and multinuclear Pt complexes. Reaction kinetics and structural changes induced by these novel Pt drugs are discussed in relation to cisplatin. NMR studies of non-DNA platinum drug targets including peptides, proteins and phospholipid membranes are also treated.

Potentiometric and spectroscopic evidence for co-ordination of dimethyltin(IV) to phosphate groups of DNA fragments and related ligands

The co-ordination of dimethyltin(IV) to 5′-GMP, 5′-ATP and 5′-d(CGCGCG)2 and to their sugar constituents (D-ribose and 2-deoxy-D-ribose) was investigated in aqueous solution by means of potentiometric titration and 1H and 31P NMR spectroscopic methods. The results showed that in acidic media the phosphate groups can provide suitable sites for metal ion co-ordination, while the hydroxy groups of the sugars or the sugar moieties of the two nucleotides play a role in this process at higher pH. The base moieties of 5′-GMP and 5′-ATP were not co-ordinated to dimethyltin(IV). The stability constants of the complexes formed in the above systems were determined by pH-metric titration. The data revealed a stronger co-ordination ability of the triphosphate as compared with that of the monophosphate. The comparison of the stability constants of the D-ribose and 2-deoxy-D-ribose complexes showed that more stable species were formed when neighbouring alcoholic hydroxy groups were available for co-ordination. The observed chemical shift changes of the 31P NMR resonances, as compared with those measured for the metal-free systems, demonstrated that the phosphate groups of the DNA fragment 5′-d(CGCGCG)2 chains act as binding sites for dimethyltin(IV) between pH 4.5 and 7. The 1- and 2-D 1H NMR spectra indicated that the base and sugar moieties do not participate in the co-ordination process under these conditions.

Interaction of cis- and trans-RuCl2(DMSO)4 with the nucleotides GpA, d(GpA), ApG, d(ApG) and d(CCTGGTCC): high-field NMR characterization of the reaction products

Abstract Both cis- and trans-RuCl2(DMSO)4 (cis-Ru and trans-Ru) react with ApG, GpA, d(ApG) and d(GpA) to yield products with bifunctional metal coordination of the bases. For each dinucleotide one major product and several minor species are formed. This is in contrast to previous results on analogous reactions between trans-Ru and d(GpG) where a substantial amount of an intermediate species was found. The rates of reaction between dinucleotides and cis-Ru are approximately 20-fold slower than for trans-Ru. The compounds formed with the two isomers exhibit identical proton NMR spectra, suggesting the same coordination mode for ruthenium in the final product. The two purine bases are coordinated to ruthenium through N7 in a head-to-head conformation with the glycosidic angles being in the anti range. Coupling constants indicate a relatively pure 3′-endo conformation for the 5′-sugar and mainly 2′-endo for the 3′-sugar. The similar bifunctional binding mode of cis- and trans-Ru(II) with dinucleotides as evident from the NMR spectra are in contrast to the different mode of interaction suggested earlier for cis- and trans-Ru complexes with DNA. trans-Ru interacts with the deoxyoctanucleotide d(CCTGGTCC), giving two main products during the first 2 h of incubation time. Four H8 guanine resonances are shifted downfield, characteristic of N7 metal coordination. The products are not analyzed in detail, but it is suggested that the structures may be described as two chiral G(N7/N7) chelates.

Detection of malignant tumours by multivariate analysis of proton magnetic resonance spectra of serum

Proton magnetic resonance spectra of blood serum have been subjected to multivariate data analysis to discriminate between samples from cancer patients and from controls. The main feature was the use of digitally defined resonance profiles. The methyl and methylene lipoprotein signals centred at 1.3 and 0.9 parts per million are non-lorentzian composite peaks that cannot be described properly by the line width at half-height. Instead 71 and 76 data points were used to describe the methylene and methyl peak profiles, respectively. These data points were used as input to a principal component analysis to distinguish between malignant (n = 29) and control samples (n = 55). At a probability level of 0.01 (F-test) modelling classified all patients except 2 correctly, while 1 control was slightly above the predictive level for malignancy.