Reversible addition of the OH radical to p-cymene in the gas phase : kinetic analysis assuming formation of a single adduct. Part 1

A flash photolysis-resonance fluorescence (FP-RF) technique was employed to study the kinetics and mechanism of the reaction of OH radicals with p-cymene at temperatures between 297 and 413 K in helium buffer gas. FP-RF experiments involved time-resolved detection of OH radicals by RF following vacuum-UV flash photolysis of H2O–p-cymene–He and H2O–He mixtures. Biexponential functions were fitted to decays of OH radicals according to reversible addition of OH radicals to p-cymene to form a single adduct. A rate constant of (15.7 ± 1.1) × 10−12 is obtained (in units of cm3 s−1) at room temperature (298 K) for the sum of the addition and abstraction channels (k1a + k1b) according to this simplified model. The Arrhenius plot reveals the step function typical of other aromatics and can be described using the expressions: 2 × 10−13 exp(+1300 K/T) at temperatures between 297 K and 324 K and 10−11 exp(−250 K/T) at temperatures between 345 K and 413 K. After consideration of the abstraction channel an equilibrium constant of k1a/k−1a = 6 × 10−26 exp(+9700 K/T) cm3 is obtained at temperatures between 297 and 325 K and 2 × 10−36 exp(+17 000 K/T) cm3 at temperatures between 325 and 380 K

Kinetic study of the reaction of OH with CH2I2

Flash photolysis (FP) coupled to resonance fluorescence (RF) was used to measure the absolute rate coefficients (k1) for the reaction of OH(X2P) radicals with diiodomethane (CH2I2) over the temperature range 295374 K. The experiments involved time-resolved RF detection of the OH (A2∑+→X2Π transition at λ = 308 nm) following FP of the H2O/CH2I 2/He mixtures. The OH(X2Π) radicals were produced by FP of H2O in the vacuum-UV at wavelengths l 4 120 nm. Decays of OH radicals in the presence of CH2I2 are observed to be exponential, and the decay rates are found to be linearly dependent on the CH2I 2 concentration. The results are described by the Arrhenius expression k1(T) = (4.2 ± 0.5) × 1011 exp[-(670 ± 20)K/T] cm3 molecule-1 s-1. The implications of the reported kinetic results for understanding the atmospheric chemistry of CH2I2 are discussed. © 2011 the Owner Societies

Discovery of novel triple helical DNA intercalators by an integrated virtual and actual screening platform

Virtual Screening is an increasingly attractive way to discover new small molecules with potential medicinal value. We introduce a novel strategy that integrates use of the molecular docking software Surflex with experimental validation by the method of competition dialysis. This integrated approach was used to identify ligands that selectively bind to the triplex DNA poly(dA)-[poly(dT)]2. A library containing ∼2 million ligands was virtually screened to identify compounds with chemical and structural similarity to a known triplex intercalator, the napthylquinoline MHQ-12. Further molecular docking studies using compounds with high structural similarity resulted in two compounds that were then demonstrated by competition dialysis to have a superior affinity and selectivity for the triplex nucleic acid than MHQ-12. One of the compounds has a different chemical backbone than MHQ-12, which demonstrates the ability of this strategy to ‘scaffold hop’ and to identify small molecules with novel binding properties. Biophysical characterization of these compounds by circular dichroism and thermal denaturation studies confirmed their binding mode and selectivity. These studies provide a proof-of-principle for our integrated screening strategy, and suggest that this platform may be extended to discover new compounds that target therapeutically relevant nucleic acid morphologies

On the stratospheric chemistry of hydrogen cyanide

HCN profiles measured by solar occultation spectrometry during 10 balloon flights of the JPL MkIV instrument are presented. The HCN profiles reveal a compact correlation with stratospheric tracers. Calculations with a 2D-model using established rate coefficients for the reactions of HCN with OH and O(^1D) severely underestimate the measured HCN in the middle and upper stratosphere. The use of newly available rate coefficients for these reactions gives reasonable agreement of measured and modeled HCN. An HCN yield of ∼30% from the reaction of CH_3CN with OH is consistent with the measurements

Purine twisted-intercalating nucleic acids: a new class of anti-gene molecules resistant to potassium-induced aggregation

Sequence-specific targeting of genomic DNA by triplex-forming oligonucleotides (TFOs) is a promising strategy to modulate in vivo gene expression. Triplex formation involving G-rich oligonucleotides as third strand is, however, strongly inhibited by potassium-induced TFO self-association into G-quartet structures. We report here that G-rich TFOs with bulge insertions of (R)-1-O-[4-(1-pyrenylethynyl)-phenylmethyl] glycerol (called twisted intercalating nucleic acids, TINA) show a much lower tendency to aggregate in potassium than wild-type analogues do. We designed purine-motif TINA–TFOs for binding to a regulatory polypurine-polypyrimidine (pur/pyr) motif present in the promoter of the KRAS proto-oncogene. The binding of TINA–TFOs to the KRAS target has been analysed by electrophoresis mobility shift assays and DNase I footprinting experiments. We discovered that in the presence of potassium the wild-type TFOs did not bind to the KRAS target, differently from the TINA analogues, whose binding was observed up to 140 mM KCl. The designed TINA–TFOs were found to abrogate the formation of a DNA–protein complex at the pur/pyr site and to down-regulate the transcription of CAT driven by the murine KRAS promoter. Molecular modelling of the DNA/TINA–TFO triplexes are also reported. This study provides a new and promising approach to create TFOs to target in vivo the genome

Evaluation of molecular descriptors for antitumor drugs with respect to noncovalent binding to DNA and antiproliferative activity

34 pages, 6 additional files, 5 tables, 4 figures.[Background ] Small molecules that bind reversibly to DNA are among the antitumor drugs currently used in chemotherapy. In the pursuit of a more rational approach to cancer chemotherapy based upon these molecules, it is necessary to exploit the interdependency between DNA-binding affinity, sequence selectivity and cytotoxicity. For drugs binding noncovalently to DNA, it is worth exploring whether molecular descriptors, such as their molecular weight or the number of potential hydrogen acceptors/donors, can account for their DNA-binding affinity and cytotoxicity.[Results] Fifteen antitumor agents, which are in clinical use or being evaluated as part of the National Cancer Institute’s drug screening effort, were analyzed in silico to assess the contribution of various molecular descriptors to their DNA-binding affinity, and the capacity of the descriptors and DNA-binding constants for predicting cell cytotoxicity. Equations to predict drug-DNA binding constants and growth-inhibitory concentrations were obtained by multiple regression following rigorous statistical procedures.[Conclusions] For drugs binding reversibly to DNA, both their strength of binding and their cytoxicity are fairly predicted from molecular descriptors by using multiple regression methods. The equations derived may be useful for rational drug design. The results obtained agree with that compounds more active across the National Cancer Institute’s 60-cell line data set tend to have common structural features.Supported by a grant from the former Spanish Ministry of Education and Science (BFU2007-60998) and the FEDER program of the European Community.Peer reviewe

The phosphate clamp: a small and independent motif for nucleic acid backbone recognition

The 1.7 Å X-ray crystal structure of the B-DNA dodecamer, [d(CGCGAATTCGCG)]2 (DDD)-bound non-covalently to a platinum(II) complex, [{Pt(NH3)3}2-µ-{trans-Pt(NH3)2(NH2(CH2)6NH2)2}](NO3)6 (1, TriplatinNC-A,) shows the trinuclear cation extended along the phosphate backbone and bridging the minor groove. The square planar tetra-am(m)ine Pt(II) units form bidentate N-O-N complexes with OP atoms, in a Phosphate Clamp motif. The geometry is conserved and the interaction prefers O2P over O1P atoms (frequency of interaction is O2P > O1P, base and sugar oxygens > N). The binding mode is very similar to that reported for the DDD and [{trans-Pt(NH3)2(NH2(CH2)6(NH3+)}2-µ-{trans-Pt(NH3)2(NH2(CH2)6NH2)2}](NO3)8 (3, TriplatinNC), which exhibits in vivo anti-tumour activity. In the present case, only three sets of Phosphate Clamps were found because one of the three Pt(II) coordination spheres was not clearly observed and was characterized as a bare Pt2+ ion. Based on the electron density, the relative occupancy of DDD and the sum of three Pt(II) atoms in the DDD-1 complex was 1:1.69, whereas the ratio for DDD-2 was 1:2.85, almost the mixing ratio in the crystallization drop. The high repetition and geometric regularity of the motif suggests that it can be developed as a modular nucleic acid binding device with general utility

A sensing mechanism for the detection of carbon nanotubes using selective photoluminescent probes based on ionic complexes with organic dyes

The multifunctional properties of carbon nanotubes (CNTs) make them a powerful platform for unprecedented innovations in a variety of practical applications. As a result of the surging growth of nanotechnology, nanotubes present a potential problem as an environmental pollutant, and as such, an efficient method for their rapid detection must be established. Here, we propose a novel type of ionic sensor complex for detecting CNTs – an organic dye that responds sensitively and selectively to CNTs with a photoluminescent signal. The complexes are formed through Coulomb attractions between dye molecules with uncompensated charges and CNTs covered with an ionic surfactant in water. We demonstrate that the photoluminescent excitation of the dye can be transferred to the nanotubes, resulting in selective and strong amplification (up to a factor of 6) of the light emission from the excitonic levels of CNTs in the near-infrared spectral range, as experimentally observed via excitation-emission photoluminescence (PL) mapping. The chirality of the nanotubes and the type of ionic surfactant used to disperse the nanotubes both strongly affect the amplification; thus, the complexation provides sensing selectivity towards specific CNTs. Additionally, neither similar uncharged dyes nor CNTs covered with neutral surfactant form such complexes. As model organic molecules, we use a family of polymethine dyes with an easily tailorable molecular structure and, consequently, tunable absorbance and PL characteristics. This provides us with a versatile tool for the controllable photonic and electronic engineering of an efficient probe for CNT detection