Adjusting the Structure of β-Cyclodextrin to Improve Complexation of Anthraquinone-Derived Drugs

β-Cyclodextrin (CD) derivatives containing an aromatic triazole ring were studied as potential carriers of the following drugs containing an anthraquinone moiety: anthraquinone-2-sulfonic acid (AQ2S); anthraquinone-2-carboxylic acid (AQ2CA); and a common anthracycline, daunorubicin (DNR). UV-Vis and voltammetry measurements were carried out to determine the solubilities and association constants of the complexes formed, and the results revealed the unique properties of the chosen CDs as effective pH-dependent drug complexing agents. The association constants of the drug complexes with the CDs containing a triazole and lipoic acid (βCDLip) or galactosamine (βCDGAL), were significantly larger than that of the native βCD. The AQ2CA and AQ2S drugs were poorly soluble, and their solubilities increased as a result of complex formation with βCDLip and βCDGAL ligands. AQ2CA and AQ2S are negatively charged at pH 7.4. Therefore, they were less prone to form an inclusion complex with the hydrophobic CD cavity than at pH 3 (characteristic of gastric juices) when protonated. The βCDTriazole and βCDGAL ligands were found to form weaker inclusion complexes with the positively charged drug DNR at an acidic pH (pH 5.5) than in a neutral medium (pH 7.4) in which the drug dissociates to its neutral, uncharged form. This pH dependence is favorable for antitumor applications.

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Adjusting the Structure of β-cyclodextrin to Improve Complexation of Anthraquinone-derived Drugs

10.20944/preprints202109.0343.v1 ◽

2021 ◽

Author(s):

Agata Krzak ◽

Olga Swiech ◽

Maciej Majdecki ◽

Renata Bilewicz

Keyword(s):

Stability Constants ◽

Ph Dependence ◽

Triazole Ring ◽

Complexing Agents ◽

Neutral Medium ◽

Medium Ph ◽

Beta Cyclodextrin ◽

The Stability ◽

Positively Charged ◽

Form Inclusion Complex

β-cyclodextrin (CD) derivatives containing aromatic triazole ring were studied as potential carriers of drugs containing an anthraquinone moiety in the structure: anthraquinone-2-sulfonic acid (AQ2S), anthraquinone-2-carboxylic acid (AQ2CA) and a common anthracycline, daunorubicin (DNR). UV-Vis and voltammetry measurements were carried out to determine the solubilities and stability constants of the complexes formed and revealed the unique properties of the chosen CDs as effective pH dependent drug complexing agents. The stability constants of the drug complexes with the CDs containing triazole: βCDLip and βCDGAL were significantly larger than with the native βCD. The AQ2CA and AQ2S drugs are ill-soluble and their solubilities increased as the result of complex formation with βCDLip and βCDGAL ligands. AQ2CA, AQ2S were negatively charged at pH 7.4 and therefore they were less prone to form inclusion complex with the hydrophobic CD cavity than at pH 3 (characteristic of gastric juices) when they were protonated. βCDTriazole and βCDGAL ligands were found to form weaker inclusion complexes with the positively charged drug DNR at acidic pH (pH 5.5) than in the neutral medium (pH 7.4) when the drug dissociates to the neutral, uncharged form. This pH dependence is favorable for anti-tumor applications.

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Rationalizing the pH-Activity Response for Escherichia Coli’s Glycinamide Ribonucleotidetransformylase Through Computational Methods

10.26434/chemrxiv.7985618.v1 ◽

2019 ◽

Author(s):

Adrian Roitberg ◽

Pancham Lal Gupta

Keyword(s):

Transfer Reaction ◽

Catalytic Mechanism ◽

Ph Dependence ◽

Ph Effects ◽

Dependent Manner ◽

E Coli ◽

Gar Tfase ◽

Activity Curve ◽

Ph Dependent ◽

Formyl Transfer

<div>Human Glycinamide ribonucleotide transformylase (GAR Tfase), a regulatory enzyme in the de novo purine biosynthesis pathway, has been established as an anti-cancer target. GAR Tfase catalyzes the formyl transfer reaction from the folate cofactor to the GAR ligand. In the present work, we study E. coli GAR Tfase, which has high sequence similarity with the human GAR Tfase with most functional residues conserved. E. coli GAR Tfase exhibits structural changes and the binding of ligands that varies with pH which leads to change the rate of the formyl transfer reaction in a pH-dependent manner. Thus, the inclusion of pH becomes essential for the study of its catalytic mechanism. Experimentally, the pH-dependence of the kinetic parameter kcat is measured to evaluate the pH-range of enzymatic activity. However, insufficient information about residues governing the pH-effects on the catalytic activity leads to ambiguous assignments of the general acid and base catalysts and consequently its catalytic mechanism. In the present work, we use pH-replica exchange molecular dynamics (pH-REMD) simulations to study the effects of pH on E. coli GAR Tfase enzyme. We identify the titratable residues governing the pH-dependent conformational changes in the system. Furthermore, we filter out the protonation states which are essential in maintaining the structural integrity, keeping the ligands bound and assisting the catalysis. We reproduce the experimental pH-activity curve by computing the population of key protonation states. Moreover, we provide a detailed description of residues governing the acidic and basic limbs of the pH-activity curve.</div>

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Enhanced Analytic Approach for Describing pH Triggered Fast Drug Release Systems

Current Drug Delivery ◽

10.2174/1567201818999210112181853 ◽

2021 ◽

Vol 18 ◽

Author(s):

Aykut Elmas ◽

Guliz Akyuz ◽

Ayhan Bergal ◽

Muberra Andac ◽

Omer Andac

Keyword(s):

Drug Release ◽

Ph Dependence ◽

Slope Angle ◽

Ph Sensitive ◽

Analytic Model ◽

Two Dimensional ◽

Analytic Equation ◽

One Dimensional ◽

Ph Dependent ◽

Fast Release

Background: pH sensitive dendrimers attached to nanocarriers, as one of the drug release systems, has become quite popular due to their ease of manufacture in experimental conditions and ability to generate fast drug release in the targeted area. This kind of fast release behavior cannot be represented properly most of the existing kinetic mathematical models. Besides, these models have either no pH dependence or pH dependence added separately. So, they have remained one dimensional. Objective: The aim of this study was to establish the proper analytic equation to describe the fast release of drugs from pH sensitive nanocarrier systems. Then, to combine it with the pH dependent equation for establishing a two-dimensional model for whole system. Methods: We used four common kinetic models for comparison and we fitted them to the release data. Finding that, only Higuchi and Korsmeyer-Peppas models show acceptable fit results. None of these models have pH dependence. To get a better description for pH triggered fast release, we observed the behavior of the slope angle of the release curve. Then we puroposed a new analytic equation by using relation between the slope angle and time. Result: To add a pH dependent equation, we assumed the drug release is “on” or “off” above/below specific pH value and we modified a step function to get a desired behavior. Conclusion: Our new analytic model shows good fitting, not only one-dimensional time dependent release, but also two-dimensional pH dependent release, that provides a useful analytic model to represent release profiles of pH sensitive fast drug release systems.

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Systematic exploration of the pH dependence of a peptide hydrogel

Canadian Journal of Chemistry ◽

10.1139/cjc-2018-0419 ◽

2019 ◽

Vol 97 (6) ◽

pp. 430-434 ◽

Cited By ~ 2

Author(s):

Natashya Falcone ◽

Tsuimy Shao ◽

Xiaoyi Sun ◽

Heinz-Bernhard Kraatz

Keyword(s):

Mechanical Strength ◽

Narrow Range ◽

Ph Dependence ◽

Stimuli Responsive ◽

Systematic Exploration ◽

Ph Conditions ◽

Ph Dependent ◽

Functional Biomaterials ◽

Peptide Hydrogel

Stimuli-responsive peptide gels are a growing class of functional biomaterials that are involved in many applications in research. Here, we present a novel di-peptide hydrogel from the compound Boc–Phe–Trp–OH in various buffer and pH conditions. We examine the effects of different stimuli, including temperature and pH, on the mechanical strength of the gels through frequency rheology studies. We found that this hydrogelator is highly pH dependent, only forming a gel in a narrow range of pH 6–7. This hydrogelator hold promise for the development of new stimuli-responsive biomaterials for specific applications that require this type of specific stimuli.

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Dynamics of Primary Events in the Photocycle of Excited Bacteriorhodopsin

Acta Biochimica et Biophysica Sinica ◽

10.1093/abbs/36.11.724 ◽

2004 ◽

Vol 36 (11) ◽

pp. 724-728 ◽

Cited By ~ 1

Author(s):

Jun-Jun Lu ◽

Ming Ming ◽

Yi Yang ◽

Jia Wu ◽

Bo Li ◽

...

Keyword(s):

Dynamic Behavior ◽

Time Scale ◽

Excitation Wavelength ◽

Ultrafast Dynamics ◽

Medium Ph ◽

Pump Probe ◽

Dynamical Behaviors ◽

Retinal Chromophore ◽

Ph Dependent ◽

The One

Abstract Transient dynamic behavior of the excited bacteriorhodopsin (BR), which was isolated from the strain H. salinarum, was studied at excitation wavelength from 585 to 639 nm. With the one-color femtosecond (fs) pump-probe technique, we revealed the primary events in BR's photocycle that took place in an ultrafast time scale. From the analysis of the decay components of the dynamical traces, it was evident that the isomerization of the retinal chromophore in BR and the intermediate J's formation occurred within 500 fs. BR exhibited pH-dependent dynamical behaviors. When the medium pH was between 5 and 9, the BR ultrafast dynamics has no obvious change. In contrast, the dynamical curves were obviously affected when the pH was out of that region.

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Preparation and Characterization of Self-Dispersing Phthalocyanine Blue 15:4 Pigment for Dyeing of Wool Textiles

Coatings ◽

10.3390/coatings10080741 ◽

2020 ◽

Vol 10 (8) ◽

pp. 741

Author(s):

Lun Nie ◽

Guangtao Chang ◽

Ruoxin Li

Keyword(s):

Sulfonic Acid ◽

Coupling Reaction ◽

Acid Dyes ◽

Light Fastness ◽

Grade 5 ◽

Weather Resistance ◽

Sulfonic Acid Groups ◽

Positively Charged ◽

Better Than

A self-dispersing pigment was produced by a diazonium coupling reaction; the pigment reacted with aromatic diazonium salts which were generated by the reaction of p-aminobenzene sulfonic acid and sodium nitrite. The surface of the pigment particles was negatively charged due to sulfonic acid groups on the pigment surface. The pigment particle size and zeta potential were, respectively, 134.5 nm and −45.4 mV at neutral pH. The wool surface was positively charged by adjusting the pH; then the anionic self-dispersing pigment dyed the cationic wool. The results show that self-dispersing pigment can adhere well without a binder, and that the K/S value is closely related to pH, dyeing time, and the amount of pigment. The color fastness of the wool was good and the light fastness of the wool was grade 5, which is better than acid dyes. Self-dispersing pigments are potential candidates for dyeing high-weather-resistance textiles.

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pH-dependent Perforation of Macrophage Phagosomes by Listeriolysin O from Listeria monocytogenes

Journal of Experimental Medicine ◽

10.1084/jem.186.7.1159 ◽

1997 ◽

Vol 186 (7) ◽

pp. 1159-1163 ◽

Cited By ~ 173

Author(s):

Kathryn E. Beauregard ◽

Kyung-Dall Lee ◽

R. John Collier ◽

Joel A. Swanson

Keyword(s):

Listeria Monocytogenes ◽

Ph Dependence ◽

Mouse Bone Marrow ◽

Listeriolysin O ◽

Bafilomycin A1 ◽

Wild Type ◽

Major Virulence Factor ◽

Ph Dependent ◽

Vacuolar Ph

The pore-forming toxin listeriolysin O (LLO) is a major virulence factor implicated in escape of Listeria monocytogenes from phagocytic vacuoles. Here we describe the pH-dependence of vacuolar perforation by LLO, using the membrane-impermeant fluorophore 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) to monitor the pH and integrity of vacuoles in mouse bone marrow–derived macrophages. Perforation was observed when acidic vacuoles containing wild-type L. monocytogenes displayed sudden increases in pH and release of HPTS into the cytosol. These changes were not seen with LLO-deficient mutants. Perforation occurred at acidic vacuolar pH (4.9–6.7) and was reduced in frequency or prevented completely when macrophages were treated with the lysosomotropic agents ammonium chloride or bafilomycin A1. We conclude that acidic pH facilitates LLO activity in vivo.

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pH-dependent pyridoxine transport by SLC19A2 and SLC19A3: Implications for absorption in acidic microclimates

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013610 ◽

2020 ◽

Vol 295 (50) ◽

pp. 16998-17008

Author(s):

Takahiro Yamashiro ◽

Tomoya Yasujima ◽

Hamid M. Said ◽

Hiroaki Yuasa

Keyword(s):

Vitamin B1 ◽

Hek293 Cells ◽

Intestinal Epithelial ◽

Madin Darby Canine Kidney ◽

Mdckii Cells ◽

Charge Selectivity ◽

Acidic Conditions ◽

Ph Dependent ◽

Darby Canine Kidney ◽

Positively Charged

SLC19A2 and SLC19A3, also known as thiamine transporters (THTR) 1 and 2, respectively, transport the positively charged thiamine (vitamin B1) into cells to enable its efficient utilization. SLC19A2 and SLC19A3 are also known to transport structurally unrelated cationic drugs, such as metformin, but whether this charge selectivity extends to other molecules, such as pyridoxine (vitamin B6), is unknown. We tested this possibility using Madin-Darby canine kidney II (MDCKII) cells and human embryonic kidney 293 (HEK293) cells for transfection experiments, and also using Caco-2 cells as human intestinal epithelial model cells. The stable expression of SLC19A2 and SLC19A3 in MDCKII cells (as well as their transient expression in HEK293 cells) led to a significant induction in pyridoxine uptake at pH 5.5 compared with control cells. The induced uptake was pH-dependent, favoring acidic conditions over neutral to basic conditions, and protonophore-sensitive. It was saturable as a function of pyridoxine concentration, with an apparent Km of 37.8 and 18.5 μm, for SLC19A2 and SLC19A3, respectively, and inhibited by the pyridoxine analogs pyridoxal and pyridoxamine as well as thiamine. We also found that silencing the endogenous SLC19A3, but not SLC19A2, of Caco-2 cells with gene-specific siRNAs lead to a significant reduction in carrier-mediated pyridoxine uptake. These results show that SLC19A2 and SLC19A3 are capable of recognizing/transporting pyridoxine, favoring acidic conditions for operation, and suggest a possible role for these transporters in pyridoxine transport mainly in tissues with an acidic environment like the small intestine, which has an acidic surface microclimate.

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A pH-dependent conformational transition of Aβ peptide and physicochemical properties of the conformers in the glial cell

Biochemical Journal ◽

10.1042/bj3610547 ◽

2002 ◽

Vol 361 (3) ◽

pp. 547-556 ◽

Cited By ~ 13

Author(s):

Yoichi MATSUNAGA ◽

Nobuhiro SAITO ◽

Akihiro FUJII ◽

Junichi YOKOTANI ◽

Tadakazu TAKAKURA ◽

...

Keyword(s):

Glial Cell ◽

Conformational Changes ◽

Conformational Transition ◽

Early Stage ◽

Ph Dependence ◽

Amyloid Β ◽

Proteinase K ◽

Aβ Peptide ◽

Ph Dependent ◽

Insight Into

In the present study we identified the epitopes of antibodies against amyloid β-(1–42)-peptide (Aβ1–42): 4G8 reacted with peptides corresponding to residues 17–21, 6F/3D reacted with peptides corresponding to residues 9–14, and anti 5-10 reacted with peptides corresponding to residues 5–10. The study also yielded some insight into the Aβ1–42 structures resulting from differences in pH. An ELISA study using monoclonal antibodies showed that pH-dependent conformational changes occur in the 6F/3D and 4G8 epitopes modified at pH 4.6, but not in the sequences recognized by anti 1-7 and anti 5-10. This was unique to Aβ1–40 and Aβ1–42 and did not occur with Aβ1–16 or Aβ17–42. The reactivity profile of 4G8 was not affected by blockage of histidine residues of pH-modified Aβ1–40 and Aβ1–42 with diethyl pyrocarbonate; however, the mutant [Gln11]Aβ1–40 abrogated the unique pH-dependence towards 4G8 observed with Aβ1–40. These findings suggest that these epitopes are cryptic at pH4.6, and that Glu11 is responsible for the changes. We suggest that the abnormal folding of 6F/3D epitope affected by pH masked the 4G8 epitope. A study of the binding of metal ions to Aβ1–42 suggested that Cu2+ and Zn2+ induced a conformational transition around the 6F/3D region at pH7.4, but did not affect the region when it was modified at pH4.6. However, Fe2+ had no effect, irrespective of pH. Aβ modified at pH 4.6 appeared to be relatively resistant to proteinase K compared with Aβs modified at pH7.4, and the former might be preferentially internalized and accumulated in a human glial cell. Our findings suggest the importance of microenvironmental changes, such as pH, in the early stage of formation of Aβ aggregates in the glial cell.

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