Photosensitized oxidative DNA damage: from hole injection to chemical product formation and strand cleavage

Oxidatively generated damage to DNA induced by a pyrenyl photosensitizer residue (Py) covalently attached to a guanine base in the DNA sequence context 5'-d(CAT[G1Py]CG2TCCTAC) in aerated solutions was monitored from the initial one-electron transfer, or hole injection step, to the formation of chemical end-products monitored by HPLC, mass spectrometry, and high-resolution gel electrophoresis. Hole injection into the DNA was initiated by two-photon excitation of the Py residue with 355 nm laser pulses, thus producing the radical cation Py*+ and hydrated electrons; the latter are trapped by O2, thus forming the superoxide anion O2*-. The decay of the Py*+ radical is correlated with the appearance of the G*+/G(-H)* radical on microsecond time scales, and O2*- combines with guanine radicals at G1 to form alkali-labile 2,5-diamino-4H-imidazolone lesions (Iz1Py). Product formation in the modified strand is smaller by a factor of 2.4 in double-stranded than in single-stranded DNA. In double-stranded DNA, hot piperidine-mediated cleavage at G2 occurs only after G1Py, an efficient hole trap, is oxidized thus generating tandem lesions. An upper limit of hole hopping rates, khh < 5 x 103 s-1 from G1*+-Py to G2 can be estimated from the known rates of the combination reaction of the G(-H)* and O2*- radicals. The formation of Iz products in the unmodified complementary strand compared to the modified strand in the duplex is approximately 10 times smaller. The formation of tandem lesions is observed even at low levels of irradiation corresponding to "single-hit" conditions when less than approximately 10% of the oligonucleotide strands are damaged. A plausible mechanism for this observation is discussed.     

Mechanisms of oxidation of guanine in DNA by carbonate radical anion, a decomposition product of nitrosoperoxycarbonate

Peroxynitrite is produced during inflammation and combines rapidly with carbon dioxide to yield the unstable nitrosoperoxycarbonate, which decomposes (in part) to CO(3) (.-) and (.)NO(2) radicals. The CO(3) (.-) radicals oxidize guanine bases in DNA through a one-electron transfer reaction process that ultimately results in the formation of stable guanine oxidation products. Here we have explored these mechanisms, starting with a spectroscopic study of the kinetics of electron transfer from 20-22mer double-stranded oligonucleotides to CO(3) (.-) radicals, together with the effects of base sequence on the formation of the end-products in runs of one, two, or three contiguous guanines. The distributions of these alkali-labile lesions were determined by gel electrophoresis methods. The cascade of events was initiated through the use of 308 nm XeCl excimer laser pulses to generate CO(3) (.-) radicals by an established method based on the photodissociation of persulfate to sulfate radicals and the oxidation of bicarbonate. Although the Saito model (Saito et al., J. Am. Chem. Soc. 1995, 117, 6406-6407) predicts relative ease of one-electron oxidations in DNA, following the trend 5'-GGG > 5'-GG > 5'-G, we found that the rate constants for CO(3) (.-)-mediated oxidation of guanines in these sequence contexts (k(5)) showed only small variation within a narrow range [(1.5-3.0)x10(7) M(-1) s(-1)]. In contrast, the distributions of the end-products are dependent on the base sequence context and are higher at the 5'-G in 5'-GG sequences and at the first two 5'-guanines in the 5'-GGG sequences. These effects are attributed to a combination of initial hole distributions among the contiguous guanines and the subsequent differences in chemical reaction yields at each guanine. The lack of dependence of k(5) on sequence context indicates that the one-electron oxidation of guanine in DNA by CO(3) (.-) radicals occurs by an inner-sphere mechanism.     

Reversible transformation of ZnII coordination geometry in a single crystal of porous metal-organic framework [Zn3(ntb)2(EtOH)2].4 EtOH

A 3D porous metal-organic framework [Zn3(ntb)2(EtOH)2]n.4nEtOH (1) that generates 1D channels of honeycomb aperture has been prepared by the solvothermal reaction of Zn(NO3)(2).6 H2O and 4,4',4'-nitrilotrisbenzoic acid (H3NTB) in EtOH at 110 degrees C. Framework 1 exhibits reversible single-crystal-to-single-crystal transformations upon removal and rebinding of the coordinating EtOH as well as the EtOH guest molecules, which give rise to desolvated crystal [Zn3(ntb)2]n (1') and resolvated crystal [Zn3(ntb)2-(EtOH)2]n.4nEtOH (1'). The X-ray structures indicate that 3D host framework is retained during the transformations from 1 to 1' and from 1' to 1', but the coordination geometry of ZnII ions changes from/to trigonal bipyramid to/from tetrahedron, concomitant with the rotational rearrangement of a carboxylate plane of the NTB3- relative to its associated phenyl ring. To retain the single crystal integrity, extensive cooperative motions must exist between the molecular components throughout the crystal. Framework 1' exhibits permanent porosity, thermal stability up to 400 degrees C, and blue luminescence, and high storage capabilities for N2, H2, CO2, and CH4.     

Synthetic 6-O-methylglucose-containing polysaccharides (sMGPs): design and synthesis

With the hope of mimicking the chemical and biological properties of natural 6-O-methyl-D-glucose-containing polysaccharides (MGPs), synthetic 6-O-methyl-D-glucose-containing polysaccharides (sMGPs) were designed and synthesized from alpha-, beta-, and gamma-cyclodextrins (CDs). The synthetic route proved to be flexible and general, to furnish a series of sMGPs ranging from 6-mer to 20-mer. A practical and scalable method was discovered selectively to cleave the CD derivatives and furnish the linear precursors to the glycosyl donors and acceptors. The Mukaiyama glycosidation was adopted to couple the glycosyl donors with the glycosyl acceptors. Unlike in the 3-O-methyl-D-mannose-containing polysaccharide (sMMP) series, the amount of the Mukaiyama acid required in the sMGP series increased with an increase of substrate size; that is, for large oligomers, more than one equivalent of the acid was required.     

Anthraquinones, Cdc25B phosphatase inhibitors, isolated from the roots of Polygonum multiflorum Thunb

Three anthraquinones, Cdc25B phosphatase inhibitors, were isolated from the methanolic extract of the roots of Polygonum multiflorum Thunb. (Polygonaceae). Anthraquinones, physcion (1), emodin (2), and questin (3), inhibited the enzymatic activity of Cdc25B phosphatase with IC(50) values of 62.5, 30, and 34 microg mL(-1), respectively. Emodin (2) and questin (3) strongly inhibited the growth of human colon cancer cells, SW620 with GI(50) values of 6.1 and 0.9 microg mL(-1), respectively. Commercially available anthraquinones, chrysophanol (4), and rhein (5) also inhibited Cdc25B phosphatase with IC(50) values of 10.7 and 22.1 microg mL(-1), respectively.     

Phase‐transition characteristics of amphiphilic poly(2‐ethyl‐2‐oxazoline)/poly(ε‐caprolactone) block copolymers in aqueous solutions

Amphiphilic diblock and triblock copolymers of various block compositions based on hydrophilic poly(2‐ethyl‐2‐oxazoline) (PEtOz) and hydrophobic poly(ε‐caprolactone) were synthesized. The micelle formation of these block copolymers in aqueous media was confirmed by a fluorescence technique and dynamic light scattering. The critical micelle concentrations ranged from 35.5 to 4.6 mg/L for diblock copolymers and 4.7 to 9.0 mg/L for triblock copolymers, depending on the block composition. The phase‐transition behaviors of the block copolymers in concentrated aqueous solutions were investigated. When the temperature was increased, aqueous solutions of diblock and triblock copolymers exhibited gel–sol transition and precipitation, both of which were thermally reversible. The gel–sol transition‐ and precipitation temperatures were manipulated by adjustment of the block composition. As the hydrophobic portion of block copolymers became higher, a larger gel region was generated. In the presence of sodium chloride, the phase transitions were shifted to a lower temperature level. Sodium thiocyanate displaced the gel region and precipitation temperatures to a higher temperature level. The low molecular weight saccharides, such as glucose and maltose, contributed to the shift of phase‐transition temperatures to a lower temperature level, where glucose was more effective than maltose in lowering the gel–sol transition temperatures. The malonic acid that formed hydrogen bonds with the PEtOz shell of micelles was effective in lowering phase‐transition temperatures to 1.0M, above which concentration the block copolymer solutions formed complex precipitates. © 2000 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 38: 2400–2408, 2000     

SIM(2)-invariant modifications of electrodynamic theory

In the Cohen–Glashow Very Special Relativity we exhibit possible modifications to the Maxwell theory and to the quantum electrodynamics Lagrangian in some generality, and discuss characteristic features depending on the modifications. Modified gauge transformations in SIM(2)-invariant theories are introduced and the related gauge fields, with two polarization states, can have nonzero mass. Also considered are SIM(2)-covariant modifications to the Proca-type field equations for a massive spin-1 particle.     

Enhanced Hydrogen Storage by Palladium Nanoparticles Fabricated in a Redox‐Active Metal–Organic Framework

Quick on the uptake : Palladium nanoparticles were fabricated simply by immersing {[Zn₃(ntb)₂(EtOH)₂]?4 EtOH}_n ( 1 ) in an MeCN solution of Pd(NO₃)₂ at room temperature, without any extra reducing agent. 3 wt % PdNPs@[ 1 ]^0.54+(NO₃^?)_0.54 significantly increase H₂ uptake capacities, both at 77 K and 1 bar and at 298 K and high pressures (see picture, red curve) compared to [Zn₃(ntb)₂]_n (black). ntb=4,4′,4′′‐nitrilotrisbenzoate.

     

All‐in‐One Target‐Cell‐Specific Magnetic Nanoparticles for Simultaneous Molecular Imaging and siRNA Delivery

Cancer‐cell‐targeted gene silencing was observed with a magnetic‐nanoparticle platform (MEIO, magnetism‐engineered iron oxide) on which a fluorescent dye, siRNA, and a RGD‐peptide targeting moiety were attached (see picture). The different functionalities enable the macroscopic (magnetic resonance) and microscopic (fluorescence) imaging of target cells. This system may be suitable for concurrent diagnostic and therapeutic applications.