scholarly journals Mechanism-based inhibitors of SIRT2: structure–activity relationship, X-ray structures, target engagement, regulation of α-tubulin acetylation and inhibition of breast cancer cell migration

2020 ◽  
Author(s):  
Alexander L. Nielsen ◽  
Nima Rajabi ◽  
Norio Kudo ◽  
Kathrine Lundø ◽  
Carlos Moreno-Yruela ◽  
...  
Keyword(s):  
Drug Target ◽  
Water Soluble ◽  
Target Engagement ◽  
X Ray ◽  
Tubulin Acetylation ◽  
Structure Activity ◽  
Complex Functions ◽  
Lysine Residues ◽  
Chain Acyl ◽  
Single Compound

ABSTRACTSirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. It affects diverse biological functions in the cell and has been considered a drug target in relation to both neurodegenerative diseases and cancer. Therefore, access to well-characterized and robust tool compounds is essential for the continued investigation of the complex functions of this enzyme. Here, we report a collection of probes that are potent, selective, stable in serum, water-soluble, amenable to cell culture experiments, and inhibit both SIRT2 deacetylation and demyristoylation. Compared to the current landscape of SIRT2 inhibitors, this is a unique ensemble of features built into a single compound. We expect the developed chemotypes to find broad application in the interrogation of SIRT2 functions in both healthy and diseased cells, and to provide a foundation for the development of future therapeutics.

scholarly journals Mechanism-based inhibitors of SIRT2: structure–activity relationship, X-ray structures, target engagement, regulation of α-tubulin acetylation and inhibition of breast cancer cell migration

2021 ◽  
Author(s):  
Alexander L. Nielsen ◽  
Nima Rajabi ◽  
Norio Kudo ◽  
Kathrine Lundø ◽  
Carlos Moreno-Yruela ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Living Cells ◽  
Cancer Cell Migration ◽  
Target Engagement ◽  
Small Peptide ◽  
X Ray ◽  
Tubulin Acetylation ◽  
Structure Activity ◽  
Lysine Residues ◽  
Chain Acyl

Sirtuin 2 (SIRT2) is a protein deacylase enzyme that removes acetyl groups and longer chain acyl groups from post-translationally modified lysine residues. Here, we developed small peptide-based inhibitors of its activity in living cells in culture.

scholarly journals X-ray crystal structure and specificity of the Toxoplasma gondii ME49 TgAPN2

2020 ◽  
Vol 477 (19) ◽  
pp. 3819-3832
Author(s):  
Emilia M. Marijanovic ◽  
Karolina Weronika Swiderska ◽  
James Andersen ◽  
Jasmin C. Aschenbrenner ◽  
Chaille T. Webb ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Toxoplasma Gondii ◽  
Drug Target ◽  
Structure And Function ◽  
Parasitic Disease ◽  
Vaccine Candidates ◽  
X Ray ◽  
Structure Activity ◽  
Comparative Structure ◽  
And Function

Toxoplasmosis is a parasitic disease caused by infection with Toxoplasma gondii that currently has few therapeutic options. The M1 aminopeptidase enzymes have been shown to be attractive targets for anti-parasitic agents and/or vaccine candidates, suggesting potential to re-purpose inhibitors between parasite M1 aminopeptidase targets. The M1 aminopeptidase TgAPN2 has been suggested to be a potential new drug target for toxoplasmosis. Here we investigate the structure and function of TgAPN2, a homologue of the antimalarial drug target PfA-M1, and evaluate the capacity to use inhibitors that target PfA-M1 against TgAPN2. The results show that despite a similar overall fold, the TgAPN2 has a unique substrate specificity and inhibition profile. Sequence and structure differences are investigated and show how comparative structure-activity relationships may provide a route to obtaining potent inhibitors of TgAPN2.

Nitrogen and Sulfur Co-doped Fluorescent Carbon Dots for the Detection of Morin and Cell Imaging

2018 ◽  
Vol 15 (1) ◽  
pp. 47-55
Author(s):  
Xuebing Li ◽  
Haifen Yang ◽  
Ning Wang ◽  
Tijian Sun ◽  
Wei Bian ◽  
...  
Keyword(s):  
Microwave Heating ◽  
Fluorescent Probe ◽  
Fluorescence Intensity ◽  
Carbon Dots ◽  
Cell Imaging ◽  
Water Soluble ◽  
Heating Process ◽  
X Ray ◽  
Doped Carbon Dots ◽  
Co Doped

Background: Morin has many pharmacological functions including antioxidant, anticancer, anti-inflammatory, and antibacterial effects. It is commonly used in the treatment of antiviral infection, gastropathy, coronary heart disease and hepatitis B in clinic. However, researches have shown that morin is likely to show prooxidative effects on the cells when the amount of treatment is at high dose, leading to the decrease of intracellular ATP levels and the increase of necrosis process. Therefore, it is necessary to determine the concentration of morin in biologic samples. Method: Novel water-soluble and green nitrogen and sulfur co-doped carbon dots (NSCDs) were prepared by a microwave heating process with citric acid and L-cysteine. The fluorescence spectra were collected at an excitation wavelength of 350 nm when solutions of NSCDs were mixed with various concentrations of morin. Results: The as-prepared NSCDs were characterized by transmission electron microscopy, X-ray diffraction and X-ray photoelectron spectroscopy. The fluorescence intensity of NSCDs decreased significantly with the increase of morin concentration. The fluorescence intensity of NSCDs displayed a linear response to morin in the concentration 0.10-30 μM with a low detection limit of 56 nM. The proposed fluorescent probe was applied to analysis of morin in human body fluids with recoveries of 98.0-102%. Conclusion: NSCDs were prepared by a microwave heating process. The present analytical method is sensitive to morin. The quenching process between NSCDs and morin is attributed to the static quenching. In addition, the cellular toxicity on HeLa cells indicated that the as-prepared NSCDs fluorescent probe does not show obvious cytotoxicity in cell imaging. Our proposed method possibly opens up a rapid and nontoxic way for preparing heteroatom doped carbon dots with a broad application prospect.

scholarly journals Fusarins G–L with Inhibition of NO in RAW264.7 from Marine-Derived Fungus Fusarium solani 7227

Marine Drugs ◽  
2021 ◽  
Vol 19 (6) ◽  
pp. 305
Author(s):  
Guangyuan Luo ◽  
Li Zheng ◽  
Qilin Wu ◽  
Senhua Chen ◽  
Jing Li ◽  
...  
Keyword(s):  
Fusarium Solani ◽  
2D Nmr ◽  
Inflammatory Activity ◽  
Raw264.7 Cells ◽  
Spectroscopic Methods ◽  
X Ray ◽  
X Ray Crystallography ◽  
Structure Activity ◽  
Ic50 Values ◽  
New Compounds

Six new fusarin derivatives, fusarins G–L (1–6), together with five known compounds (5–11) were isolated from the marine-derived fungus Fusarium solani 7227. The structures of the new compounds were elucidated by means of comprehensive spectroscopic methods (1D and 2D NMR, HRESIMS, ECD, and ORC) and X-ray crystallography. Compounds 5–11 exhibited potent anti-inflammatory activity by inhibiting the production of NO in RAW264.7 cells activated by lipopolysaccharide, with IC50 values ranging from 3.6 to 32.2 μM. The structure–activity relationships of the fusarins are discussed herein.

scholarly journals The Influence of Varying Fluorination Patterns on the Thermodynamics and Kinetics of Benzenesulfonamide Binding to Human Carbonic Anhydrase II

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 509 ◽  
Author(s):  
Steffen Glöckner ◽  
Khang Ngo ◽  
Björn Wagner ◽  
Andreas Heine ◽  
Gerhard Klebe
Keyword(s):  
Carbonic Anhydrase ◽  
Carbonic Anhydrase Ii ◽  
The Novel ◽  
Binding Modes ◽  
X Ray ◽  
Structure Activity ◽  
Small Set ◽  
Novel Method ◽  
Human Carbonic Anhydrase ◽  
Kinetics Of

The fluorination of lead-like compounds is a common tool in medicinal chemistry to alter molecular properties in various ways and with different goals. We herein present a detailed study of the binding of fluorinated benzenesulfonamides to human Carbonic Anhydrase II by complementing macromolecular X-ray crystallographic observations with thermodynamic and kinetic data collected with the novel method of kinITC. Our findings comprise so far unknown alternative binding modes in the crystalline state for some of the investigated compounds as well as complex thermodynamic and kinetic structure-activity relationships. They suggest that fluorination of the benzenesulfonamide core is especially advantageous in one position with respect to the kinetic signatures of binding and that a higher degree of fluorination does not necessarily provide for a higher affinity or more favorable kinetic binding profiles. Lastly, we propose a relationship between the kinetics of binding and ligand acidity based on a small set of compounds with similar substitution patterns.

Water soluble biguanide salts and their 1,3,5-triazine derivatives as inhibitors of acetylcholinesterase and α-glucosidase

2020 ◽  
Vol 235 (10) ◽  
pp. 465-475
Author(s):  
Ozge Gungor ◽  
Seda Nur Kertmen Kurtar ◽  
Muhammet Kose
Keyword(s):  
Spectroscopic Method ◽  
Substitute Aniline ◽  
Water Soluble ◽  
X Ray Diffraction ◽  
Nucleophilic Reaction ◽  
X Ray ◽  
Triazine Derivatives ◽  
Acidic Conditions ◽  
Approved Drugs ◽  
Solid State Structures

AbstractSeven biguanide derivatives were prepared by the nucleophilic reaction between dicyandiamide and p-substitute aniline derivatives or memantine or adamantine under acidic conditions. The cyclization of the biguanide compounds were also conducted via acetone to give 1,3,5-triazine derivatives. The structures of the synthesized compounds were characterized by analytical methods. The solid state structures of [HL5]Cl, [H2L7]Cl2, [HL1a]Cl and [HL5a]Cl were investigated by X-ray diffraction study. The acetylcholinesterase and α-glucosidase inhibitor properties of the compounds were then evaluated by the spectroscopic method. The compounds were found to show considerable acetylcholinesterase and α-glucosidase inhibitory activities compared to the approved drugs. The cyclization of biguanide derivatives with acetone did not affect inhibition of acetylcholinesterase, yet increased the α-glucosidase inhibition.

scholarly journals Influence of Salt Support Structures on Material Jetted Aluminum Parts

Materials ◽  
2021 ◽  
Vol 14 (15) ◽  
pp. 4072
Author(s):  
Benedikt Kirchebner ◽  
Maximilian Ploetz ◽  
Christoph Rehekampff ◽  
Philipp Lechner ◽  
Wolfram Volk
Keyword(s):  
Molten Salts ◽  
Laser Scanning ◽  
Water Soluble ◽  
Laser Scanning Microscopy ◽  
Confocal Laser ◽  
Support Structures ◽  
Micro Hardness ◽  
X Ray ◽  
Melting Temperatures ◽  
Economic Support

Like most additive manufacturing processes for metals, material jetting processes require support structures in order to attain full 3D capability. The support structures have to be removed in subsequent operations, which increases costs and slows down the manufacturing process. One approach to this issue is the use of water-soluble support structures made from salts that allow a fast and economic support removal. In this paper, we analyze the influence of salt support structures on material jetted aluminum parts. The salt is applied in its molten state, and because molten salts are typically corrosive substances, it is important to investigate the interaction between support and build material. Other characteristic properties of salts are high melting temperatures and low thermal conductivity, which could potentially lead to remelting of already printed structures and might influence the microstructure of aluminum that is printed on top of the salt due to low cooling rates. Three different sample geometries have been examined using optical microscopy, confocal laser scanning microscopy, energy-dispersive X-ray spectroscopy and micro-hardness testing. The results indicate that there is no distinct influence on the process with respect to remelting, micro-hardness and chemical reactions. However, a larger dendrite arm spacing is observed in aluminum that is printed on salt.

scholarly journals Characterizing the structure–activity relationships of natural products, tanshinones, reveals their mode of action in inhibiting spleen tyrosine kinase

RSC Advances ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 2453-2461
Author(s):  
Min-Che Tung ◽  
Keng-Chang Tsai ◽  
Kit-Man Fung ◽  
Ming-Jaw Don ◽  
Tien-Sheng Tseng
Keyword(s):  
Natural Products ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Mode Of Action ◽  
Drug Target ◽  
Receptor Protein ◽  
Inflammatory Disorder ◽  
Spleen Tyrosine Kinase ◽  
Structure Activity Relationships ◽  
Structure Activity

The cytosolic non-receptor protein kinase, spleen tyrosine kinase (SYK), is an attractive drug target in autoimmune, inflammatory disorder, and cancers indications.

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