scholarly journals Excited-State Intramolecular Hydrogen Transfer of Compact Molecules Controls Amyloid Aggregation Profiles

2021 ◽  
Author(s):  
Mannkyu Hong ◽  
Mingeun Kim ◽  
Jiwon Yoon ◽  
Seung-Hee Lee ◽  
Mu-Hyun Baik ◽  
...  
Keyword(s):  
Excited State ◽  
Hydrogen Transfer ◽  
Experimental Studies ◽  
Amyloid Β ◽  
Molecular Structures ◽  
Hydroxyl Groups ◽  
Chemical Reagents ◽  
Amyloidogenic Peptides ◽  
Intramolecular Hydrogen

Designing new chromophores by tuning their molecular structures and optimizing their photophysical properties leads to suitable photochromic features. Herein, we report a series of anthraquinone (AQ)-based photosensitizers that undergoes excited-state intramolecular hydrogen transfer and effectively oxidizes amyloidogenic peptides, which significantly affects the subsequent aggregation pathways. DFT calculations showed that the appropriate position of the hydroxyl groups in the AQ backbone and the consequent intramolecular hydrogen transfer can facilitate the energy transfer to triplet oxygen. Biochemical and biophysical investigations confirmed that these photoactive chemical reagents are able to oxidatively modify both metal-free amyloid-β (Aβ) and metal-bound Aβ, thereby redirecting their on-pathway aggregation into off-pathway as well as disassembling their pre-formed aggregates. Moreover, the in vivo histochemical analysis of Aβ species produced upon photoactivation of the most promising candidate demonstrated that they do not aggregate into toxic oligomeric or fibrillar aggregates in the brain. Overall, our combined computational and experimental studies validate a light-based approach for designing small molecules as chemical reagents targeting and controlling amyloidogenic peptides associated with neurodegenerative disorders.

Thiosemicarbazonate complexes with affinity for amyloid-β fibers: synthesis, characterization and biological studies

2019 ◽  
Vol 11 (19) ◽  
pp. 2527-2546 ◽  
Author(s):  
Arantxa Pino-Cuevas ◽  
Paula D Raposinho ◽  
Célia Fernandes ◽  
António Paulo ◽  
Ulrich Abram ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Blood Brain Barrier ◽  
Free Ligand ◽  
Amyloid Β ◽  
Molecular Structures ◽  
X Ray Diffraction ◽  
X Ray ◽  
Biological Studies ◽  
Similar Affinity

Aim: Obtain radioimages of amyloid-β fibers using 99mTc-complexes. Methodology: Tridentate thiosemicarbazone and thiocarbonohydrazone ligands containing fragments (stilbene, azobenzene, benzothiazole or benzoxazole) with affinity for amyloid-ß fibers and its Re(I) complexes have been prepared. The molecular structures of several ligands and complexes were determined by x-ray diffraction. Binding affinity studies toward Aß1-42 fibers were performed for the ligands and Re(I) complexes. The ability of formation of some 99mTc(I) complexes, their biodistribution and in vivo stability have been established. Results & conclusion: Complexes of stilbene and benzothiazole thiosemicarbazonates show similar affinity for amyloid-β fibers to the free ligand. These 99mTc complexes present a reasonable in vivo stability and a low capability to cross the blood–brain barrier although not sufficient to brain amyloid imaging.

Intramolekulare Wasserstoffverschiebung in der Hexosephosphatisomerase-Reaktion bei der photosynthetischen Stärkebildung in Chlorella

1966 ◽  
Vol 21 (6) ◽  
pp. 557-562 ◽  
Author(s):  
Hans-Dieter Dorrer ◽  
Carl Fedtke ◽  
Achim Trebst
Keyword(s):  
Hydrogen Transfer ◽  
Chlorella Pyrenoidosa ◽  
Starch Biosynthesis ◽  
Strong Indication ◽  
Exchange Reactions ◽  
Carbon 14 ◽  
Multienzyme System ◽  
Intramolecular Hydrogen

Chlorella pyrenoidosa was illuminated in the presence of glucose and fructose echa having carbon-14 and tritium markers. Starch and sucrose were degraded to obtain the intramulocular distribution of 14C and tritium. Glucose-1-14C-2-T was incorporated into the glucose of starch and into the glucose moiety of sucrose without change of the T/14C ratio. Fructose-1-14C-1-T (labelled stereospecifically in the isomerase position) was incorporated into starch, yielding predominately glucose-1-14C-2-T, whereas fructose-1-14C-1-T (labelled in the nonisomerase position) gave mainly glucose-1-14C-1-T.The results, in particular the transfer of tritium from C-1 of fructose to C-2 of glucose, are interpreted as being a strong indication for an intramolecular hydrogen transfer in the hexosephosphat-isomerase reaction in a multienzyme system of the photosynthetic starch biosynthesis in vivo, shielding the hexoses of T-exchange reactions with water.

scholarly journals Ab initio studies of two pyrimidine derivatives as possible photo-switch systems

Open Physics ◽  
2013 ◽  
Vol 11 (9) ◽  
Author(s):  
András Csehi ◽  
Clemens Woywod ◽  
Gábor Halász ◽  
Ágnes Vibók
Keyword(s):  
Excited State ◽  
Hydrogen Transfer ◽  
Covalent Bond ◽  
Excitation Energies ◽  
Complete Active Space ◽  
Vertical Excitation ◽  
Singlet States ◽  
Self Consistent Field ◽  
Intramolecular Hydrogen ◽  
Vertical Excitation Energies

AbstractThe six lowest lying electronic singlet states of 8-(pyrimidine-2-yl)quinolin-ol and 2-(4-nitropyrimidine-2-yl)ethenol have been studied theoretically using the complete active space self-consistent-field (CASSCF) and M’ller-Plesset second-order perturbation theory (MP2) methods. Both molecules can be viewed as consisting of a frame and a crane component. As a possible mechanism for the excited-state relaxation process an intramolecular hydrogen transfer promoted by twisting around the covalent bond connecting the molecular frame and crane moieties has been considered. Based on this idea we have attempted to derive abstracted photochemical pathways for both systems. Geometry optimizations for the construction of hypothetical reaction coordinates have been performed at the MP2 level of theory while the CASSCF approach has been employed for the calculation of vertical excitation energies along the pathways. The results of the calculations along the specific twisting displacements investigated in this study do not support the notion of substantial twisting activity upon excitation of any of the five excited states at the planar terminal structures of the torsion coordinates of both molecules. However, the present analysis should be considered only as a first, preliminary step towards an understanding of the photochemistry of the two candidate compounds. For example, we have not performed any excited state geometry optimizations so far and the estimates of vertical excitation energies do not take dynamical electron correlation into account. Further work on this subject is in progress.

scholarly journals Probing Competing Relaxation Pathways in Malonaldehyde with Transient X-Ray Absorption Spectroscopy

2020 ◽  
Author(s):  
Nanna Holmgaard List ◽  
Adrian L. Dempwolff ◽  
Andreas Dreuw ◽  
Patrick Norman ◽  
Todd J. Martínez
Keyword(s):  
Excited State ◽  
Absorption Spectroscopy ◽  
Hydrogen Transfer ◽  
Intersystem Crossing ◽  
Light Sources ◽  
X Ray ◽  
Valence States ◽  
Specific Mapping ◽  
Intramolecular Hydrogen ◽  
X Ray Absorption

<p>Excited-state intramolecular hydrogen transfer (ESIHT) is a fundamental reaction relevant to chemistry and biology. Malonaldehyde is the simplest example of ESIHT, yet only little is known experimentally about its excited-state dynamics. Several competing relaxation pathways have been proposed, including internal conversion mediated by ESIHT and C=C torsional motion as well as intersystem crossing. We perform an in silico transient X-ray absorption spectroscopy (TRXAS) experiment at the oxygen K-edge to investigate its potential to monitor the proposed ultrafast decay pathways in malonaldehyde upon photoexcitation to its bright S2(pp*) state. We employ both restricted active space perturbation theory and algebraic diagrammatic construction for the polarization propagator along interpolated reaction coordinates as well as representative trajectories from ab initio multiple spawning simulations to compute the TRXAS signals from the lowest valence states. Our study suggests that oxygen K-edge TRXAS can distinctly fingerprint the passage through the H-transfer intersection and the concomitant population transfer to the S1(np*) state. Potential intersystem crossing to T1(pp*) is detectable from reappearance of the double pre-edge signature and reversed intensities. Moreover, the torsional deactivation pathway induces transient charge redistribution from the enol side towards the central C-atom and manifests itself as substantial shifts of the pre-edge features. Given the continuous advances in X-ray light sources, our study proposes an experimental route to disentangle ultrafast excited-state decay channels in this prototypical ESIHT system and provides a pathway-specific mapping of the TRXAS signal to facilitate the interpretation of future experiments.</p>

scholarly journals Probing Competing Relaxation Pathways in Malonaldehyde with Transient X-Ray Absorption Spectroscopy

2020 ◽  
Author(s):  
Nanna Holmgaard List ◽  
Adrian L. Dempwolff ◽  
Andreas Dreuw ◽  
Patrick Norman ◽  
Todd J. Martínez
Keyword(s):  
Excited State ◽  
Absorption Spectroscopy ◽  
Hydrogen Transfer ◽  
Intersystem Crossing ◽  
Light Sources ◽  
X Ray ◽  
Valence States ◽  
Specific Mapping ◽  
Intramolecular Hydrogen ◽  
X Ray Absorption

<p>Excited-state intramolecular hydrogen transfer (ESIHT) is a fundamental reaction relevant to chemistry and biology. Malonaldehyde is the simplest example of ESIHT, yet only little is known experimentally about its excited-state dynamics. Several competing relaxation pathways have been proposed, including internal conversion mediated by ESIHT and C=C torsional motion as well as intersystem crossing. We perform an in silico transient X-ray absorption spectroscopy (TRXAS) experiment at the oxygen K-edge to investigate its potential to monitor the proposed ultrafast decay pathways in malonaldehyde upon photoexcitation to its bright S2(pp*) state. We employ both restricted active space perturbation theory and algebraic diagrammatic construction for the polarization propagator along interpolated reaction coordinates as well as representative trajectories from ab initio multiple spawning simulations to compute the TRXAS signals from the lowest valence states. Our study suggests that oxygen K-edge TRXAS can distinctly fingerprint the passage through the H-transfer intersection and the concomitant population transfer to the S1(np*) state. Potential intersystem crossing to T1(pp*) is detectable from reappearance of the double pre-edge signature and reversed intensities. Moreover, the torsional deactivation pathway induces transient charge redistribution from the enol side towards the central C-atom and manifests itself as substantial shifts of the pre-edge features. Given the continuous advances in X-ray light sources, our study proposes an experimental route to disentangle ultrafast excited-state decay channels in this prototypical ESIHT system and provides a pathway-specific mapping of the TRXAS signal to facilitate the interpretation of future experiments.</p>

Insights into amyloid disease from fly models

2014 ◽  
Vol 56 ◽  
pp. 69-83 ◽  
Author(s):  
Ko-Fan Chen ◽  
Damian C. Crowther
Keyword(s):  
Drosophila Melanogaster ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Disease Pathogenesis ◽  
Amyloid Aggregates ◽  
Aβ Amyloid ◽  
Polypeptide Chains ◽  
Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

Toxicity of Heparinoids, with Special Reference to the Precipitation of Fibrinogen

1964 ◽  
Vol 12 (01) ◽  
pp. 232-261 ◽  
Author(s):  
S Sasaki ◽  
T Takemoto ◽  
S Oka
Keyword(s):  
Molecular Weight ◽  
Dextran Sulfate ◽  
Anticoagulant Activity ◽  
Molecular Structures ◽  
Severe Reaction ◽  
Clinical Use ◽  
Molecular Weights ◽  
Close Relationship

SummaryTo demonstrate whether the intravascular precipitation of fibrinogen is responsible for the toxicity of heparinoid, the relation between the toxicity of heparinoid in vivo and the precipitation of fibrinogen in vitro was investigated, using dextran sulfate of various molecular weights and various heparinoids.1. There are close relationships between the molecular weight of dextran sulfate, its toxicity, and the quantity of fibrinogen precipitated.2. The close relationship between the toxicity and the precipitation of fibrinogen found for dextran sulfate holds good for other heparinoids regardless of their molecular structures.3. Histological findings suggest strongly that the pathological changes produced with dextran sulfate are caused primarily by the intravascular precipitates with occlusion of the capillaries.From these facts, it is concluded that the precipitates of fibrinogen with heparinoid may be the cause or at least the major cause of the toxicity of heparinoid.4. The most suitable molecular weight of dextran sulfate for clinical use was found to be 5,300 ~ 6,700, from the maximum value of the product (LD50 · Anticoagulant activity). This product (LD50 · Anticoagulant activity) can be employed generally to assess the comparative merits of various heparinoids.5. Clinical use of the dextran sulfate prepared on this basis gave satisfactory results. No severe reaction was observed. However, two delayed reactions, alopecia and thrombocytopenia, were observed. These two reactions seem to come from the cause other than intravascular precipitation.

Inhibition of Amyloid β Aggregation Using Optimized Nano-Encapsulated Formulations of Plant Extracts with High Metal Chelator Activities

2020 ◽  
Vol 21 (8) ◽  
pp. 681-701
Author(s):  
Fatma Kazdal ◽  
Fatemeh Bahadori ◽  
Burak Celik ◽  
Abdulselam Ertas ◽  
Gulacti Topcu
Keyword(s):  
Plant Extracts ◽  
Amyloid Β ◽  
Toxic Metal ◽  
In Vivo Studies ◽  
Total Phenolic ◽  
Metal Chelator ◽  
Apo E ◽  
High Metal ◽  
Induced Aggregation

Background: The role of Fe+2, Cu+2 and Zn+2 in facilitating aggregation of Amyloid β (Aβ) and consequently, the progression of Alzheimer's disease (AD) is well established. Objective: Development of non-toxic metal chelators is an emerging era in the treatment of AD, in which complete success has not been fully achieved. The purpose of this study was to determine plant extracts with high metal chelator and to encapsulate them in nano-micellar systems with the ability to pass through the Blood Brain Barrier (BBB). Method: Extracts of 36 different Anatolian plants were prepared, total phenolic and flavonoid contents were determined, and the extracts with high content were examined for their Fe+2, Cu+2 and Zn+2 chelating activities. Apolipoprotein E4 (Apo E) decorated nano-formulations of active extracts were prepared using Poly (Lactide-co-Glycolide) (PLGA) (final product ApoEPLGA) to provide BBB penetrating property. Results: Verbascum flavidum aqueous extract was found as the most active sample, incubation of which, with Aβ before and after metal-induced aggregation, resulted in successful inhibition of aggregate formation, while re-solubilization of pre-formed aggregates was not effectively achieved. The same results were obtained using ApoEPLGA. Conclusion: An optimized metal chelator nano-formulation with BBB penetrating ability was prepared and presented for further in-vivo studies.

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