scholarly journals Expanding the Scope of the Cleavable N-(Methoxy)oxazolidine Linker for the Synthesis of Oligonucleotide Conjugates

Molecules ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 490
Author(s):  
Aapo Aho ◽  
Antti Äärelä ◽  
Heidi Korhonen ◽  
Pasi Virta
Keyword(s):  
Peptide Nucleic Acid ◽  
Dna Aptamer ◽  
Published Data ◽  
Ph Responsive ◽  
Automated Assembly ◽  
Cleavage Rate ◽  
Acidic Conditions ◽  
The Stability ◽  
Simple Conversion ◽  
Oligonucleotide Conjugates

Oligonucleotides modified by a 2′-deoxy-2′-(N-methoxyamino) ribonucleotide react readily with aldehydes in slightly acidic conditions to yield the corresponding N-(methoxy)oxazolidine-linked oligonucleotide-conjugates. The reaction is reversible and dynamic in slightly acidic conditions, while the products are virtually stable above pH 7, where the reaction is in a ‘‘switched off-state’’. Small molecular examinations have demonstrated that aldehyde constituents affect the cleavage rate of the N-(methoxy)oxazolidine-linkage. This can be utilized to adjust the stability of this pH-responsive cleavable linker for drug delivery applications. In the present study, Fmoc-β-Ala-H was immobilized to a serine-modified ChemMatrix resin and used for the automated assembly of two peptidealdehydes and one aldehyde-modified peptide nucleic acid (PNA). In addition, a triantennary N-acetyl-d-galactosamine-cluster with a β-Ala-H unit has been synthesized. These aldehydes were conjugated via N-(methoxy)oxazolidine-linkage to therapeutically relevant oligonucleotide phosphorothioates and one DNA-aptamer in 19–47% isolated yields. The cleavage rates of the conjugates were studied in slightly acidic conditions. In addition to the diverse set of conjugates synthesized, these experiments and a comparison to published data demonstrate that the simple conversion of Gly-H to β-Ala-H residue resulted in a faster cleavage of the N-(methoxy)oxazolidine-linker at pH 5, being comparable (T0.5 ca 7 h) to hydrazone-based structures.

scholarly journals A pH-Responsive Foam Formulated with PAA/Gemini 12-2-12 Complexes

2021 ◽  
Vol 5 (3) ◽  
pp. 37
Author(s):  
Hernán Martinelli ◽  
Claudia Domínguez ◽  
Marcos Fernández Leyes ◽  
Sergio Moya ◽  
Hernán Ritacco
Keyword(s):  
Surface Tension ◽  
Dynamic Surface Tension ◽  
Foam Formation ◽  
Ph Responsive ◽  
Dynamic Surface ◽  
X Ray ◽  
Equilibrium Surface Tension ◽  
Potential Applications ◽  
The Stability ◽  
Air Interfaces

In the search for responsive complexes with potential applications in the formulation of smart dispersed systems such as foams, we hypothesized that a pH-responsive system could be formulated with polyacrylic acid (PAA) mixed with a cationic surfactant, Gemini 12-2-12 (G12). We studied PAA-G12 complexes at liquid–air interfaces by equilibrium and dynamic surface tension, surface rheology, and X-ray reflectometry (XRR). We found that complexes adsorb at the interfaces synergistically, lowering the equilibrium surface tension at surfactant concentrations well below the critical micelle concentration (cmc) of the surfactant. We studied the stability of foams formulated with the complexes as a function of pH. The foams respond reversibly to pH changes: at pH 3.5, they are very stable; at pH > 6, the complexes do not form foams at all. The data presented here demonstrate that foam formation and its pH responsiveness are due to interfacial dynamics.

Role of Antibiotic Lock Therapy for the Treatment of Catheter-Related Bloodstream Infections

2009 ◽  
Vol 32 (9) ◽  
pp. 678-688 ◽  
Author(s):  
Jose L Del Pozo
Keyword(s):  
Antimicrobial Agents ◽  
Therapeutic Option ◽  
Bloodstream Infections ◽  
Resistance Pattern ◽  
Published Data ◽  
Sufficient Power ◽  
Lock Therapy ◽  
Antibiotic Lock ◽  
The Stability ◽  
Systemic Antibiotics

Catheter-related bloodstream infections are often difficult to treat because they are caused by organisms that embed themselves in a bio film layer on the catheter surface, resulting in an increased resistance to antimicrobial agents. Systemic antibiotics are usually administered but, although generally effective in eliminating circulating bacteria, they frequently fail to sterilize the line, leaving the patient at a continuing risk of complications or recurrence. A successful approach to managing these infections requires making an appropriate decision regarding whether the catheter should be removed or retained using antibiotic lock therapy; and choosing the type and duration of antimicrobial therapy based on the type of organism and its resistance pattern. Studies that have evaluated antibiotic lock therapy have varied in the types of antibiotics and concentrations used, the addition of heparin to the solutions, and dwell times in the catheter lumen. Guidelines from the Infectious Diseases Society of America include use of antibiotic lock therapy as a therapeutic option for intraluminal infections when the device is not removed and, although not routine, as prophylaxis for catheter-related infection in select patient populations. However, there are no published guidelines on the concentration of heparin or antibiotics that should be used, and minimal published data on the stability of heparin combinations with antibiotics. It is to be hoped that antibiotic locks will be subject to randomized controlled trials of sufficient power to confirm or refute their use.

Factors Affecting Choice of Working Stresses for High-Temperature Service

1933 ◽  
Vol 1 (3) ◽  
pp. 99-102
Author(s):  
P. G. McVetty
Keyword(s):  
High Temperature ◽  
Published Data ◽  
Creep Tests ◽  
Fundamental Study ◽  
Factors Affecting ◽  
Creep Characteristics ◽  
The Stability ◽  
Safe Working

Abstract This paper discusses the various methods which have been proposed to determine safe working stresses for high-temperature service. The question of the stability of alloys during the test and in subsequent service is considered, with particular emphasis upon probable changes in creep characteristics during long exposure to stress and temperature. It is shown that published data in general do not admit of extrapolation, and that attempts to estimate total creep in service from such data are not usually satisfactory. The author stresses the need for more fundamental study of the laws governing creep rather than creep tests of many different materials.

scholarly journals The Effects of Salts on the Stability of the Collagen Helix Under Acidic Conditions

1968 ◽  
Vol 21 (4) ◽  
pp. 821 ◽  
Author(s):  
Anne FW oodlock ◽  
BS Harrap
Keyword(s):  
Thermal Stability ◽  
Carboxyl Groups ◽  
Neutral Ph ◽  
Acid Ph ◽  
Helix Stability ◽  
Acidic Conditions ◽  
Anions And Cations ◽  
The Stability ◽  
Thermal Stability Of ◽  
Positively Charged

In the acid pH region, the relative effects of various salts on the thermal stability of the collagen helix are quite different from their effects at neutral pH. The magnitude of the decrease in thermal stability brought about by the salts studied depends mainly on the nature and concentration of the anion and very little on the nature of the cation, whereas at neutral pH the nature of both anions and cations affects the collagen helix stability, the effects of the two ions being roughly additive. The magnitude of the effect of salts at acid pH is much greater than that at neutral pH whereas for a non-ionized denaturant, urea, the magnitudes at both neutral and acid pH are similar. The data are discussed in terms of possible interactions between salts and the positively charged protein with particular consideration of the effects of salts on the pKa of protein carboxyl groups.

scholarly journals Preparation of Isotopically Labelled Standards of Creatinine Via H/D Exchange and Their Application in Quantitative Analysis by LC-MS

Molecules ◽  
2020 ◽  
Vol 25 (7) ◽  
pp. 1514
Author(s):  
Remigiusz Bąchor ◽  
Andrzej Konieczny ◽  
Zbigniew Szewczuk
Keyword(s):  
Internal Standard ◽  
Test Method ◽  
Simple Test ◽  
Liquid Chromatography Mass Spectrometry ◽  
Creatinine Concentration ◽  
Back Exchange ◽  
Acidic Conditions ◽  
Facile Preparation ◽  
The Stability ◽  
Neutral Conditions

Kidneys play a crucial role in maintaining metabolic homeostasis in a body. Serum creatinine concentration is a simple test used as an indicator of renal function. One of the known ways of quantifying creatinine concentration is the liquid chromatography-mass spectrometry (LC-MS) method, using an isotopically labeled analog of creatinine as an internal standard. Unfortunately, such isotope-labeled analogs are expensive and their synthesis is complex. Here we demonstrate a facile preparation of deuterated analogues of creatinine, via the H/D exchange of hydrogens located at the α-carbon (α-C) of the N-methylated amino acid part, under basic conditions. The stability of retrieved isotopologues was analyzed under both neutral or acidic conditions, and the results revealed that the introduced deuterons do not undergo back-exchange. In addition, the coelution of deuterated and non-deuterated forms under acidic and neutral conditions was observed. The prepared isotopologues were successfully applied in the quantitative LC-MS analysis of urine samples, and the results demonstrated that the presented strategy is novel and inexpensive, and that the quantification correlates with the commonly used Jaffe test method.

scholarly journals Site-Specific Cleavage of RNAs Derived from the PIM1 3′-UTR by a Metal-Free Artificial Ribonuclease

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 807 ◽  
Author(s):  
Felix Zellmann ◽  
Laura Thomas ◽  
Ute Scheffer ◽  
Roland Hartmann ◽  
Michael Göbel
Keyword(s):  
Competitive Inhibition ◽  
Reaction Rates ◽  
Phosphate Esters ◽  
Rna Cleavage ◽  
Site Specificity ◽  
Cleavage Rate ◽  
Short Oligonucleotide ◽  
A Cell ◽  
Artificial Nuclease ◽  
Oligonucleotide Conjugates

Oligonucleotide conjugates of tris(2-aminobenzimidazole) have been reported previously to cleave complementary RNA strands with high levels of sequence and site specificity. The RNA substrates used in these studies were oligonucleotides not longer than 29-mers. Here we show that ~150–400-mer model transcripts derived from the 3′-untranslated region of the PIM1 mRNA reacted with rates and specificities comparable to those of short oligonucleotide substrates. The replacement of DNA by DNA/LNA mixmers further increased the cleavage rate. Tris(2-aminobenzimidazoles) were designed to interact with phosphates and phosphate esters. A cell, however, contains large amounts of phosphorylated species that may cause competitive inhibition of RNA cleavage. It is thus important to note that no loss in reaction rates was observed in phosphate buffer. This opens the way to in-cell applications for this type of artificial nuclease. Furthermore, we disclose a new synthetic method giving access to tris(2-aminobenzimidazoles) in multigram amounts.

The detrimental effect of orotic acid substitution in the peptide nucleic acid strand on the stability of PNA2:NA triple helices

2005 ◽  
Vol 83 (10) ◽  
pp. 1731-1740 ◽  
Author(s):  
Robert HE Hudson ◽  
Filip Wojciechowski
Keyword(s):  
Nucleic Acid ◽  
Carboxylic Acid ◽  
Peptide Nucleic Acid ◽  
Triple Helix ◽  
Orotic Acid ◽  
Uv Spectroscopy ◽  
Triplex Formation ◽  
Helix Formation ◽  
Triple Helix Formation ◽  
The Stability

We have investigated the incorporation of C6 derivatives of uracil into polypyrimidine peptide nucleic acid oligomers. Starting with uracil-6-carboxylic acid (orotic acid), a peptide nucleic acid monomer compatible with Fmoc-based synthesis was prepared. This monomer then served as a convertible nucleobase whereupon treatment of the resin-bound methyl orotate containing hexamers with hydroxide or amines cleanly converted the ester to an orotic acid or orotamide-containing peptide nucleic acid. Peptide nucleic acid hexamers containing the C6-modified nucleobase hybridized to both poly(riboadenylic acid) and poly(deoxyriboadenylic acid) via triplex formation. Complexes formed with poly(riboadenylic acid) were more stable than those formed with poly(dexoyriboadenylic acid), as measured by temperature-dependent UV spectroscopy. However, both of these complexes were destabilized relative to the complexes formed by an unmodified peptide nucleic acid oligomers. Internal or doubly substituted hexamers are destabilized more strongly than a terminally substituted one, and the type of substitution (carboxamide, ester, carboxylic acid) affects the overall triplex stability. These results clearly show that incorporation of a C6-substituted uracil into polypyrimidine PNA is detrimental to triplex formation. We have also extended this chemistry to incorporate uracil-5-methylcarboxylate into a peptide nucleic acid hexamer. After on-resin conversion of the C5 ester to the 3-(N,N-dimethylamino)propylamide, significant stabilization of the triplex formed with poly(riboadenylic acid) was observed, which illustrates the compatibility of C5 substitution with peptide nucleic acid directed triple helix formation. Key words: peptide nucleic acid, triple helix, orotic acid, orotamide, PNA.

scholarly journals The properties and performance of a pH-responsive functionalised nanoparticle

2014 ◽  
Vol 175 ◽  
pp. 171-187 ◽  
Author(s):  
Sandra Ast ◽  
Peter J. Rutledge ◽  
Matthew H. Todd
Keyword(s):  
Exchange Process ◽  
Ph Responsive ◽  
Disulfide Exchange ◽  
Emission Maximum ◽  
Fluorescence Measurements ◽  
And Performance ◽  
The Stability ◽  
Ph Range ◽  
Naphthalimide Dye ◽  
Over Time

We report fluorescence measurements of three quantum dots (QDs) of different sizes functionalised with the same pH responsive naphthalimide dye. QD size strongly influences energy transfer between dye and dot. Using QDs with an emission maximum of 570 nm gives rise to an interesting transfer of energy from dye to dot, while QDs with an emission maximum at 670 nm give unexpected enhancement of the dye emission. Titrations of QDs with the dye provide a means to establish the loading and hence an approximation of the surface dye density, which varies in proportion to QD size. Quenching effects are observed beyond the loading limit, and may indicate non-specific interactions between the excess dye and the nanoparticle. Attachment of the dye to the QD core is achieved by a thiol/disulfide exchange process that has been interrogated with Raman spectroscopy. The stability of these QD–dye conjugates over time and across a physiological pH range has been investigated to provide an assessment of their performance and robustness.

The effect of heating rate on the stability of stationary fluids

1967 ◽  
Vol 29 (2) ◽  
pp. 337-347 ◽  
Author(s):  
I. G. Currie
Keyword(s):  
Rayleigh Number ◽  
Surface Temperature ◽  
Fluid Layer ◽  
Critical Rayleigh Number ◽  
Lower Surface ◽  
Published Data ◽  
Heating Rates ◽  
Lower Surface Temperature ◽  
The Stability ◽  
Horizontal Fluid Layer

A horizontal fluid layer whose lower surface temperature is made to vary with time is considered. The stability analysis for this situation shows that the criterion for the onset of instability in a fluid layer which is being heated from below, depends on both the method and the rate of heating. For a fluid layer with two rigid boundaries, the minimum Rayleigh number corresponding to the onset of instability is found to be 1340. For slower heating rates the critical Rayleigh number increases to a maximum value of 1707·8, while for faster heating rates the critical Rayleigh number increases without limit.Two specific types of heating are investigated in detail, constant flux heating and linearly varying surface temperature. These cases correspond closely to situations for which published data exist. The results are in good qualitative agreement.

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