Oxidation of guanine in G, GG, and GGG sequence contexts by aromatic pyrenyl radical cations and carbonate radical anions: relationship between kinetics and distribution of alkali-labile lesions

Oxidatively generated DNA damage induced by the aromatic radical cation of the pyrene derivative 7,8,9,10-tetrahydroxytetrahydrobenzo[a]pyrene (BPT), and by carbonate radicals anions, was monitored from the initial one-electron transfer, or hole injection step, to the formation of hot alkali-labile chemical end-products monitored by gel electrophoresis. The fractions of BPT molecules bound to double-stranded 20-35-mer oligonucleotides with noncontiguous guanines G and grouped as contiguous GG and GGG sequences were determined by a fluorescence quenching method. Utilizing intense nanosecond 355 nm Nd:YAG laser pulses, the DNA-bound BPT molecules were photoionized to BPT*+ radicals by a consecutive two-photon ionization mechanism. The BPT*+ radicals thus generated within the duplexes selectively oxidize guanine by intraduplex electron-transfer reactions, and the rate constants of these reactions follow the trend 5'-..GGG.. > 5'-..GG.. > 5'-..G... In the case of CO3*- radicals, the oxidation of guanine occurs by intermolecular collision pathways, and the bimolecular rate constants are independent of base sequence context. However, the distributions of the end-products generated by CO3*- radicals, as well as by BPT*+, are base sequence context-dependent and are greater than those in isolated guanines at the 5'-G in 5'-...GG... sequences, and the first two 5'- guanines in the 5'-..GGG sequences. These results help to clarify the conditions that lead to a similar or different base sequence dependence of the initial hole injection step and the final distribution of oxidized, alkali-labile guanine products. In the case of the intermolecular one-electron oxidant CO3*-, the rate constant of hole injection is similar for contiguous and isolated guanines, but the subsequent equilibration of holes by hopping favors trapping and product formation at contiguous guanines, and the sequence dependence of these two phenomena are not correlated. In contrast, in the case of the DNA-bound oxidant BPT*+, the hole injection rate constants, as well as hole equilibration, exhibit a similar dependence on base sequence context, and are thus correlated to one another.     

Irradiation of the porphyrin causes unfolding of the protein in the protoporphyrin IX/beta-lactoglobulin noncovalent complex

Porphyrins such as protoporphyrin IX (PPIX) are known to occasionally cause conformational changes in proteins for which they are specific ligands. It has also been established that irradiation of porphyrins noncovalently intercalated between bases or bound to one of the grooves can cause conformational effects on DNA. Conversely, there is no evidence reported in the literature of conformational changes caused by noncovalently bound PPIX to globular proteins for which the porphyrin is not a specific ligand. This study shows that the irradiation of the porphyrin in the PPIX/lactoglobulin noncovalent complex indeed causes a local and limited (approximately 7%) unfolding of the protein near the location of Trp19. This event causes the intrinsic fluorescence spectrum of the protein to shift to the red by 2 nm and the average decay lifetime to lengthen by approximately 0.5 ns. The unfolding of lactoglobulin occurs only at pH >7 because of the increased instability of the protein at alkaline pH. The photoinduced unfolding does not depend on the presence of O2 in solution; therefore, it is not mediated by formation of singlet oxygen and is likely the result of electron transfer between the porphyrin and amino acid residues.     

Gold nanoparticles enhance the anti-leukemia action of a 6-mercaptopurine chemotherapeutic agent

6-mercaptopurine and its riboside derivatives are some of the most widely utilized anti-leukemic and anti-inflammatory drugs. Their short biological half-life and severe side effects limit their use. A new delivery method for these drugs based on 4-5 nm gold nanoparticles can potentially resolve these issues. We have found substantial enhancement of the antiproliferative effect against K-562 leukemia cells of Au nanoparticles bearing 6-mercaptopurine-9-beta-d-ribofuranoside compared to the same drug in typically administered free form. The improvement was attributed to enhanced intracellular transport followed by the subsequent release in lysosomes. Enhanced activity and nanoparticle carriers will make possible the reduction of the overall concentration of the drug, renal clearance, and, thus, side effects. The nanoparticles with mercaptopurine also showed excellent stability over 1 year without loss of inhibitory activity.     

Divergent reactivity of allene-containing α-diazoesters using Cu and Rh catalysis

A versatile intramolecular reaction of allene-containing diazomalonates that exhibits excellent chemoselectivity for either allenic C–H insertion or cyclopropanation is demonstrated. The identity of the product depends on the transition metal catalyst that is employed for the reaction. Rh catalysts promote exclusive C–H insertion with good diastereoselectivity for the trans product, while Cu catalysis enables intramolecular cyclopropanation to yield methylenecyclopropanes with moderate to good E:Z ratios.     

Energetic ion bombardment of Ag surfaces by C<Stack><Subscript>60</Subscript><Superscript>+</Superscript></Stack> and Ga<Superscript>+</Superscript> projectiles

The ion bombardment-induced release of particles from a metal surface is investigated using energetic fullerene cluster ions as projectiles. The total sputter yield as well as partial yields of neutral and charged monomers and clusters leaving the surface are measured and compared with corresponding data obtained with atomic projectile ions of similar impact kinetic energy. It is found that all yields are enhanced by about one order of magnitude under bombardment with the C60+ cluster projectiles compared with Ga+ ions. In contrast, the electronic excitation processes determining the secondary ion formation probability are unaffected. The kinetic energy spectra of sputtered particles exhibit characteristic differences which reflect the largely different nature of the sputtering process for both types of projectiles. In particular, it is found that under C60+ impact (1) the energy spectrum of sputtered atoms peaks at significantly lower kinetic energies than for Ga+ bombardment and (2) the velocity spectra of monomers and dimers are virtually identical, a finding which is in pronounced contrast to all published data obtained for atomic projectiles. The experimental findings are in reasonable agreement with recent molecular dynamics simulations.     

Access to Nitriles from Aldehydes Mediated by an Oxoammonium Salt

A scalable, high yielding, rapid route to access an array of nitriles from aldehydes mediated by an oxoammonium salt (4‐acetylamino‐2,2,6,6‐tetramethylpiperidine‐1‐oxoammonium tetrafluoroborate) and hexamethyldisilazane (HMDS) as an ammonia surrogate has been developed. The reaction likely involves two distinct chemical transformations: reversible silyl‐imine formation between HMDS and an aldehyde, followed by oxidation mediated by the oxoammonium salt and desilylation to furnish a nitrile. The spent oxidant can be easily recovered and used to regenerate the oxoammonium salt oxidant.     

Kinetics and mechanism for the phase transfer catalyzed cycloaddition of dichlorocarbene to cis-1,4-polybutadiene

The kinetics for the cycloaddition of dichlorocarbene to cis-1,4-polybutadiene (BR) have been examined for aqueous and solid sodium hydroxide–chloroform mixtures containing 350 molecular weight α-methyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) (Carbowax 350) as a phase transfer catalyst. This study describes the influence of reaction variables on rate and the partitioning of dichlorocarbene between dichlorocyclopropanation and hydrolysis. The results are consistent with a kinetic model derived for the case where mass transfer is not rate limiting. However, this does not apply at high conversions where mass transfer control occurs due to large increases in viscosity. Higher BR concentrations can be achieved by replacing chloroform with methylene chloride containing stoichiometric amounts of chloroform. This mass action effect causes more favorable partitioning toward cyclopropanation; otherwise, chloroform and methylene chloride behave similarly as solvents. Water is an essential component in this reaction because it greatly increases the ability of the catalyst to extract sodium hydroxide into the organic phase.     

Stereoselective synthesis of N-aryl proline amides by biotransformation-Ugi-Smiles sequence

An efficient combination of MAO-N-catalyzed desymmetrization of cyclic meso-amines with Ugi-Smiles multicomponent chemistry produced optically pure N-aryl proline amides. This method represents the first report of a fully asymmetric Ugi-Smiles process.