scholarly journals From Hydrogen Peroxide-Responsive Boronated Nucleosides Towards Antisense Therapeutics – A Computational Mechanistic Study

2019 ◽  
Vol 92 (2) ◽  
pp. 287-295
Author(s):  
Tana Tandarić ◽  
Lucija Hok ◽  
Robert Vianello
Keyword(s):  
Hydrogen Peroxide ◽  
Genetic Disorders ◽  
Md Simulations ◽  
Chemical Mechanism ◽  
Nucleophilic Attack ◽  
Mechanistic Study ◽  
Stimuli Responsive ◽  
Nucleic Acid Therapeutics ◽  
Promising Tool ◽  
Synthetic Approaches

We used a combination of MD simulations and DFT calculations to reveal the precise chemical mechanism underlying the conversion of boronated nucleosides to natural nucleosides in the presence of hydrogen peroxide, which was recently experimentally demonstrated by Morihiro and Obika et al. (Chem. Sci. 2018, 9, 1112). Our results show that this process is initiated by the H2O2 deprotonation to a base concerted with the nucleophilic attack of the resulting OOH– anion onto the boron atom as the rate-limiting step of the overall transformation. This liberates a free base, followed by the 1,2-rearrangement to the C–OOH– adduct. Lastly, breaking of the O–O bond within the peroxide moiety cleaves the boron–carbon bond, giving boronic acid ester and the matching ketone as the final products. The obtained reaction profiles successfully interpret a much higher conversion rate of the thymine derivative over its guanine analogue, and rationalize why t-Bu-hydroperoxide is hindering the conversion, thus placing both aspects in firm agreement with experiments. The offered insight represents a promising tool for the future synthetic approaches of stimuli-responsive biomolecules, especially chemically caged prodrug-type nucleic acid therapeutics, bearing significant importance due to their application potential in diagnostics and therapy of various genetic disorders.

scholarly journals Mechanistic Study of the Conversion of Superoxide to Oxygen and Hydrogen Peroxide in Carbon Nanoparticles

2016 ◽  
Vol 8 (24) ◽  
pp. 15086-15092 ◽  
Author(s):  
Almaz S. Jalilov ◽  
Chenhao Zhang ◽  
Errol L. G. Samuel ◽  
William K. A. Sikkema ◽  
Gang Wu ◽  
...  
Keyword(s):  
Hydrogen Peroxide ◽  
Carbon Nanoparticles ◽  
Mechanistic Study

scholarly journals Encapsulation and Ultrasound-Triggered Release of G-Quadruplex DNA in Multilayer Hydrogel Microcapsules

Polymers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 1342 ◽  
Author(s):  
Aaron Alford ◽  
Brenna Tucker ◽  
Veronika Kozlovskaya ◽  
Jun Chen ◽  
Nirzari Gupta ◽  
...  
Keyword(s):  
Nucleic Acids ◽  
Defense Mechanisms ◽  
The Body ◽  
Stimuli Responsive ◽  
Triggered Release ◽  
Quadruplex Dna ◽  
Nucleic Acid Therapeutics ◽  
Wide Range ◽  
G Quadruplex ◽  
Hydrogel Capsules

Nucleic acid therapeutics have the potential to be the most effective disease treatment strategy due to their intrinsic precision and selectivity for coding highly specific biological processes. However, freely administered nucleic acids of any type are quickly destroyed or rendered inert by a host of defense mechanisms in the body. In this work, we address the challenge of using nucleic acids as drugs by preparing stimuli responsive poly(methacrylic acid)/poly(N-vinylpyrrolidone) (PMAA/PVPON)n multilayer hydrogel capsules loaded with ~7 kDa G-quadruplex DNA. The capsules are shown to release their DNA cargo on demand in response to both enzymatic and ultrasound (US)-triggered degradation. The unique structure adopted by the G-quadruplex is essential to its biological function and we show that the controlled release from the microcapsules preserves the basket conformation of the oligonucleotide used in our studies. We also show that the (PMAA/PVPON) multilayer hydrogel capsules can encapsulate and release ~450 kDa double stranded DNA. The encapsulation and release approaches for both oligonucleotides in multilayer hydrogel microcapsules developed here can be applied to create methodologies for new therapeutic strategies involving the controlled delivery of sensitive biomolecules. Our study provides a promising methodology for the design of effective carriers for DNA vaccines and medicines for a wide range of immunotherapies, cancer therapy and/or tissue regeneration therapies in the future.

Diffusion of atomic oxygen relevant to water formation in amorphous interstellar ices

2014 ◽  
Vol 168 ◽  
pp. 205-222 ◽  
Author(s):  
Myung Won Lee ◽  
Markus Meuwly
Keyword(s):  
Electrostatic Interactions ◽  
Atomic Oxygen ◽  
Md Simulations ◽  
Umbrella Sampling ◽  
Chemical Mechanism ◽  
Amorphous Ice ◽  
Migration Barriers ◽  
Water Formation ◽  
Interstellar Ices ◽  
Migration Pathways

Molecular dynamics (MD) simulations together with accurate physics-based force fields are employed to determine the mobility of atomic oxygen in amorphous ice at low temperatures, characteristic for conditions in interstellar ices. From the simulations it is found that the mobility of atomic oxygen ranges from 60 to 480 Å2 ns−1 in amorphous ice at temperatures between 50 and 200 K. Hence, the simulations establish that atomic oxygen is mobile to a certain degree and a chemical mechanism for water formation involving oxygen mobility is a realistic scenario. This is also confirmed by the computed migration barriers for oxygen diffusion by multiple umbrella sampling simulations, which yield barriers for diffusion in the range of 0.7–1.9 kcal mol−1. The physics-based force field – based on a multipolar expansion of the electrostatic interactions – yields more pronounced energetics for oxygen migration pathways compared to the conventional point-charge models employed in typical simulations. Once formed, the computed solvation free energy suggests that atomic oxygen thermodynamically prefers to be localized inside amorphous ice and is available for chemical reaction, which may be relevant to water formation in and on grains.

scholarly journals pH-Sensitive Poly(β-amino ester)s Nanocarriers Facilitate the Inhibition of Drug Resistance in Breast Cancer Cells

Nanomaterials ◽  
2018 ◽  
Vol 8 (11) ◽  
pp. 952 ◽  
Author(s):  
Mengxue Zhou ◽  
Xingcai Zhang ◽  
Jin Xie ◽  
Rongxiang Qi ◽  
Huiru Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Ph Sensitive ◽  
Amino Ester ◽  
Stimuli Responsive ◽  
Glycoprotein P ◽  
Cell Internalization ◽  
Promising Tool ◽  
Intracellular Drug Delivery ◽  
Mcf 7

Multidrug resistance (MDR) remains an unmet challenge in chemotherapy. Stimuli-responsive nanocarriers emerge as a promising tool to overcome MDR. Herein, pH-sensitive poly(β-amino ester)s polymers (PHP)-based micellar nanoparticles were synthesized for enhanced doxorubicin (DOX) delivery in drug resistant breast cancer MCF-7/ADR cells. DOX-loaded PHP micelles showed rapid cell-internalization and lysosomal escape in MCF-7/ADR cells. The cytotoxicity assays showed relatively higher cell inhibition of DOX-loaded PHP micelles than that of free DOX against MCF-7/ADR cells. Further mechanistic studies showed that PHP micelles were able to inhibit P-glycoprotein (P-gp) activity by lowering mitochondrial membrane potentials and ATP levels. These results suggested that the enhanced antitumor effect might be attributed to PHP-mediated lysosomal escape and drug efflux inhibition. Therefore, PHP would be a promising pH-responsive nanocarrier for enhanced intracellular drug delivery and overcoming MDR in cancer cells.

Numerical Study on Effect of Hydrogen Peroxide Additive on Ethanol HCCI Engine

2012 ◽  
Vol 433-440 ◽  
pp. 244-250 ◽  
Author(s):  
Tian Li ◽  
Jun Deng ◽  
Tang Tang Bao ◽  
Zhi Jun Wu
Keyword(s):  
Hydrogen Peroxide ◽  
Numerical Study ◽  
Engine Performance ◽  
Chemical Mechanism ◽  
No Production ◽  
Cylinder Pressure ◽  
Ethanol Mixture ◽  
Hcci Engine ◽  
Engine Model ◽  
Production Mechanisms

In this article, based on a combined chemical mechanism with detailed ethanol oxidization and NO production mechanisms, a single cylinder ethanol HCCI engine model was established using the software CHEMKIN. Comparing with experimental data, this model can well predict cylinder pressure and NO emission. By changing mole fraction of hydrogen peroxide in initial ethanol mixture at different conditions, the effect of hydrogen peroxide additive on ethanol HCCI engine performance was investigated. The results show that hydrogen peroxide can effectively improve cylinder pressure and advance heat release progress, without notably increasing NO production.

Hydroxyl free radical production by the reaction of N-methyl-N′-nitro-N-nitrosoguanidine with hydrogen peroxide without exposure to light

1992 ◽  
Vol 70 (3-4) ◽  
pp. 262-268 ◽  
Author(s):  
Tomiko Mikuni ◽  
Masaharu Tatsuta ◽  
Mikiharu Kamachi
Keyword(s):  
Hydrogen Peroxide ◽  
Free Radical ◽  
Nucleophilic Attack ◽  
Peroxynitrous Acid ◽  
Nitrite Ion ◽  
Hydroxyl Free Radical ◽  
Spin Resonance ◽  
Resonance Spin ◽  
Layer Chromatography ◽  
Spin Trapping Technique

We examined hydroxyl free radical (∙OH) production in the mixture of H2O2 and N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) without exposure to light using the electron spin resonance spin-trapping technique. When the mixtures were protected from exposure to light, ∙OH was formed at pH 6.5 and above; it was not formed at pH 5.0 and below, consistent with our previous report. The amount of ∙OH trapped depended on the concentrations of MNNG and H2O2 and the pH. Nitrite ion was also detected colorimetrically at pH 6.5 and above, but not detected at pH 5.0 and below in the mixtures without exposure to light. Moreover, its production depended on the concentrations of MNNG and H2O2 and the pH. The formation of N-methyl-N′-nitroguanidine in the mixture at pH 7.8 was confirmed by thin-layer chromatography and melting point. These results suggest that nucleophilic attack by H2O2 on the nitroso nitrogen of MNNG results in the formation of N-methyl-N′-nitroguanidine and peroxynitrous acid, which degrades homolytically to yield ∙OH and nitrogen dioxide, resulting in the production of nitrite ion, at pH 6.5 and above without exposure to light.Key words: N-methyl-N′-nitro-N-nitrosoguanidine, hydrogen peroxide, hydroxyl free radical, peroxynitrous acid.

Photochemical Hydroxylation of Salicylic Acid with Hydrogen Peroxide; Mechanistic Study of Substrate Sensitized Reaction

1996 ◽  
Vol 61 (12) ◽  
pp. 1729-1737 ◽  
Author(s):  
Kamil Lang ◽  
Jiřina Brodilová ◽  
Stanislav Luňák
Keyword(s):  
Hydrogen Peroxide ◽  
Salicylic Acid ◽  
Quantum Yields ◽  
Mechanistic Study ◽  
Isomer Ratio ◽  
Dihydroxybenzoic Acid ◽  
Effect Of Ph ◽  
Product Ratio

The photochemical hydroxylation of salicylic acid (SA) by hydrogen peroxide proceeds via the same intermediate independently of the excited reactant (i.e. SA or H2O2). This conclusion is supported by the similar effect of pH on the quantum yields and on the isomer ratio of formed products: 2,3-dihydroxybenzoic acid (2,3-DHB) and 2,5-dihydroxybenzoic acid (2,5-DHB). The product ratio ([2,3-DHB]/[2,5-DHB]) is not affected by H2O2 concentration.

Sequence-specific cleavage of DNA via nucleophilic attack of hydrogen peroxide, assisted by flp recombinase

Biochemistry ◽  
1993 ◽  
Vol 32 (18) ◽  
pp. 4698-4701 ◽  
Author(s):  
Amy S. Kimball ◽  
Jehee Lee ◽  
Makkuni Jayaram ◽  
Thomas D. Tullius
Keyword(s):  
Hydrogen Peroxide ◽  
Nucleophilic Attack ◽  
Flp Recombinase
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