scholarly journals Esterase-Sensitive Prodrugs of a Potent Bisubstrate Inhibitor of Nicotinamide N-Methyltransferase (NNMT) Display Cellular Activity

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1357
Author(s):  
Matthijs J. van Haren ◽  
Yongzhi Gao ◽  
Ned Buijs ◽  
Roberto Campagna ◽  
Davide Sartini ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Parent Compound ◽  
Cell Permeability ◽  
Live Cells ◽  
Isopropyl Ester ◽  
Amino Acid Side Chain ◽  
Cellular Activity ◽  
Single Digit ◽  
Trimethyl Lock ◽  
The Stability

A recently discovered bisubstrate inhibitor of Nicotinamide N-methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells.

scholarly journals Photoluminescent Coordination Polymers Based on Group 12 Metals and 1H-Indazole-6-Carboxylic Acid

Inorganics ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 20
Author(s):  
Antonio A. García-Valdivia ◽  
Estitxu Echenique-Errandonea ◽  
Gloria B. Ramírez-Rodríguez ◽  
José M. Delgado-López ◽  
Belén Fernández ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Coordination Polymers ◽  
Density Functional ◽  
Free Ligand ◽  
Emission Spectra ◽  
Point Of View ◽  
Theoretical Point ◽  
Fourier Transformed Infrared Spectroscopy ◽  
3D Network ◽  
The Stability

Two new coordination polymers (CPs) based on Zn(II) and Cd(II) and 1H-indazole-6-carboxylic acid (H2L) of general formulae [Zn(L)(H2O)]n (1) and [Cd2(HL)4]n (2) have been synthesized and fully characterized by elemental analyses, Fourier transformed infrared spectroscopy and single crystal X-ray diffraction. The results indicate that compound 1 possesses double chains in its structure whereas 2 exhibits a 3D network. The intermolecular interactions, including hydrogen bonds, C–H···π and π···π stacking interactions, stabilize both crystal structures. Photoluminescence (PL) properties have shown that compounds 1 and 2 present similar emission spectra compared to the free-ligand. The emission spectra are also studied from the theoretical point of view by means of time-dependent density-functional theory (TD-DFT) calculations to confirm that ligand-centred π-π* electronic transitions govern emission of compound 1 and 2. Finally, the PL properties are also studied in aqueous solution to explore the stability and emission capacity of the compounds.

Preparation of Thymidine-4'-C-carboxylic Acid and Its Derivatives

1997 ◽  
Vol 62 (7) ◽  
pp. 1128-1135 ◽  
Author(s):  
Hubert Hřebabecký ◽  
Antonín Holý
Keyword(s):  
Carboxylic Acid ◽  
Methyl Ester ◽  
Sodium Methoxide ◽  
Isopropyl Ester ◽  
Significant Activity

3',5'-Di-O-benzoyl-4'-C-hydroxymethylthymidine (3) was prepared in four steps from 3'-O-(tert-butyldimethylsilyl)-4'-C-hydroxymethylthymidine (1). Oxidation of 3 with pyridinium dichromate afforded 3',5'-di-O-benzoylthymidine-4'-C-carboxylic acid (4) which on debenzoylation gave free thymidine-4'-C-carboxylic acid, (3R,2S,5R)-3-hydroxy-2-hydroxymethyl-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)tetrahydrofuran-2-carboxylic acid, (5). Esterification of acid 5 with diazomethane afforded the methyl ester 6. Its isopropyl ester 7 was obtained by transesterification of the methyl ester 6. Reaction of ester 6 with ammonia and hydrazine led to the respective amide 8 and hydrazide 9. Upon reaction with 1,1'-carbonyldiimidazole, the protected acid 4 was converted into the corresponding imidazolide 11, which, without isolation, was treated with glycinamide, dimethylamine and aminoethanol to give aminocarbonylmethylamide 12a, N,N-dimethylamide 13a and hydroxyethylamide 14a, respectively. The free amides 12b, 13b and 14b were obtained by methanolysis of corresponding benzoates with methanolic sodium methoxide. Neither of the prepared compounds exhibited significant activity against HIV.

scholarly journals Concomitant polymorphs of aryl-ether amine via catemer and dimer carboxylic acid supramolecular interactions and their effect on optical properties

2021 ◽  
Author(s):  
Mehboobali Pannipara ◽  
Abdullah G Al-Sehemi
Keyword(s):  
Optical Properties ◽  
Carboxylic Acid ◽  
Crystal Lattice ◽  
Functional Groups ◽  
Molecular Orbital ◽  
Acid Group ◽  
Supramolecular Interactions ◽  
Aryl Ether ◽  
Stability Calculation ◽  
The Stability

Abstract Carboxylic acid supramolecular synthon exhibited dimer or catemer motifs in the crystal lattice depend on the substituent and other functional groups present in the structure. In general, presence of other competing functional groups produced catemer motifs whereas unsubstituted acids showed dimer. In this manuscript, we have synthesized a new aryl ether amine-based Schiff base with carboxylic acid functionality ( 1 ) and demonstrated polymorphic structure via catemer ( 1a ) and dimer ( 1b ) motifs in the solid state. In both the structure, carboxylic acid group adopted different orientation in the crystal lattice. The different H-bonding lead to modulation of optical properties that was further supported highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) calculation. Further the stability calculation indicates that catemer structure was more stable by 8.54 kcal/mole relative to dimer motifs. In contrast, naphthyl group attached carboxylic acid structure did not show neither dimer nor catemer motifs in the crystal lattice as compared to diethylaminophenyl group, which confirm the presence of other substituent or competing functional groups strongly influence on the motifs of supramolecular interactions.

scholarly journals Poly(catecholamine) Coating and Biofunctionalization of CsPbBr3 Microcrystals

2021 ◽  
Author(s):  
Sangyeon Cho ◽  
Seok-Hyun Yun
Keyword(s):  
Lipid Bilayers ◽  
Environmental Stability ◽  
Live Cells ◽  
Functional Coatings ◽  
Common Strategy ◽  
Novel Method ◽  
Halide Perovskites ◽  
The Stability ◽  
New Applications

<p>Lead halide perovskites (LHP) microcrystals are promising materials for various optoelectronic applications. Surface coating on particles is a common strategy to improve their functionality and environmental stability, but LHP is not amenable to most coating chemistries because of its intrinsic weakness against polar solvents. Here, we describe a novel method of synthesizing LHP microcrystals in a super-saturated polar solvent using sonochemistry and applying various functional coatings on individual microcrystals <i>in situ</i>. We synthesize cesium lead bromine perovskite (CsPbBr<sub>3</sub>) microparticles capped with organic poly-norepinephrine (pNE) layers. The catechol group of pNE coordinates to bromine-deficient lead atoms, forming a defect-passivating and diffusion-blocking shell. The pNE layer enhances the stability of CsPbBr<sub>3</sub> in water by 2,000-folds, enabling bright luminescence and lasing from single microcrystals in water. Furthermore, the pNE shell permits biofunctionalization with proteins, small molecules, and lipid bilayers. Luminescence from CsPbBr<sub>3</sub> microcrystals is sustained in water over 1 hour and observed in live cells. The functionalization method may enable new applications of LHP particles in water-rich environments.<b></b></p>

scholarly journals Foliar application of sodium selenate induces regulation in yield formation, grain quality characters and 2-acetyl-1-pyrroline biosynthesis in fragrant rice

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Haowen Luo ◽  
Bin Du ◽  
Longxin He ◽  
Axiang Zheng ◽  
Shenggang Pan ◽  
...  
Keyword(s):  
Carboxylic Acid ◽  
Grain Yield ◽  
Grain Quality ◽  
Foliar Application ◽  
Higher Plants ◽  
Sodium Selenate ◽  
Rice Varieties ◽  
Fragrant Rice ◽  
The Stability ◽  
Heading Stage

Abstract Background Selenium (Se) is a beneficial element for higher plants and essential for mammals. To study the effect of the foliar application of sodium selenate on fragrant rice performance, a pot experiment was conducted in Guangdong, China. At the initial heading stage, one-time foliar application of sodium selenate with concentrations of 0, 10, 20, 30, 40 and 50 μmol·L− 1 (named CK, Se1, Se2, Se3, Se4 and Se5, respectively) were foliar applied on two fragrant rice varieties, ‘Meixiangzhan-2’ and ‘Xiangyaxiangzhan’. Results Selenate application at the initial heading stage not only improved the grain yield of fragrant rice by increasing the seed-setting rate and grain weight, but also promoted the grain quality by increasing crude protein contents and lowering the chalky rice rate. Furthermore, Se applications enhanced the biosynthesis of 2-acetyl-1- pyrroline (2-AP), the main aromatic compound, by increasing the contents of precursors (△1- pyrroline, proline and pyrroline-5-carboxylic acid (P5C)) and the activities of enzymes (proline dehydrogenase (PRODH), △1-pyrroline-5-carboxylic acid synthetase (P5CS), and ornithine aminotransferase (OAT)) in fragrant rice. The results also showed that foliar application of sodium selenate enhanced the antioxidant system of both varieties by promoting the activities of peroxidase (POD), superoxide dismutase (SOD), catalase (CAT) and reducing the contents of malondialdehyde (MDA). Furthermore, the real-time PCR analyses depicted that foliar application of selenate up-regulated the GPX1, GPX4 and CATC transcripts. The higher antioxidative enzymatic activities might strength the stress resistant to ensure the stability of yield in fragrant rice form abiotic stress. Conclusions Foliar applications of sodium selenate at the initial heading stage increased the grain 2-AP content by enhancing the biosynthesis-related enzymes and precursors. The grain yield and quality of fragrant rice also increased due to selenate application. Furthermore, foliar application of selenate promoted the activities of enzymes such as POD, SOD and CAT and up-regulated the expression of gene GPX4, GPX1 and CATC.

Assembly and Dynamics of the Bacterial Flagellum

2020 ◽  
Vol 74 (1) ◽  
pp. 181-200 ◽  
Author(s):  
Judith P. Armitage ◽  
Richard M. Berry
Keyword(s):  
Single Molecule ◽  
Protein Complexes ◽  
Complex Structure ◽  
Live Cells ◽  
Flagellar Motor ◽  
Interacting Protein ◽  
Bacterial Flagellum ◽  
Bacterial Flagellar Motor ◽  
The Stability

The bacterial flagellar motor is the most complex structure in the bacterial cell, driving the ion-driven rotation of the helical flagellum. The ordered expression of the regulon and the assembly of the series of interacting protein rings, spanning the inner and outer membranes to form the ∼45–50-nm protein complex, have made investigation of the structure and mechanism a major challenge since its recognition as a rotating nanomachine about 40 years ago. Painstaking molecular genetics, biochemistry, and electron microscopy revealed a tiny electric motor spinning in the bacterial membrane. Over the last decade, new single-molecule and in vivo biophysical methods have allowed investigation of the stability of this and other large protein complexes, working in their natural environment inside live cells. This has revealed that in the bacterial flagellar motor, protein molecules in both the rotor and stator exchange with freely circulating pools of spares on a timescale of minutes, even while motors are continuously rotating. This constant exchange has allowed the evolution of modified components allowing bacteria to keep swimming as the viscosity or the ion composition of the outside environment changes.

Open-Chain Crown-Ether-Derived Two-Photon Fluorescence Probe for Real-Time Dynamic Biopsy of Mercury Ions

2017 ◽  
Vol 70 (6) ◽  
pp. 705
Author(s):  
Chibao Huang ◽  
Daohai Zhang ◽  
Junle Qu ◽  
Xiaonan Liu ◽  
Guanglian Zhao ◽  
...  
Keyword(s):  
Water Solubility ◽  
Fluorescence Probe ◽  
Stokes Shift ◽  
Cell Permeability ◽  
Photon Absorption ◽  
Live Cells ◽  
Open Chain ◽  
Two Photon ◽  
Two Photon Fluorescence ◽  
Photon Fluorescence

A novel two-photon fluorescence probe for Hg2+ derived from bis(styryl)terephthalonitrile, as a two-photon fluorophore, and bis[2-(2-hydroxyethyl sulfanyl) ethyl]amino group (ionophore), as a novel Hg2+ ligand, was developed. The probe possesses small molecule size, large two-photon absorption cross-section (1067 GM) in H2O, non-cytotoxic effect, long wavelength emission at 588 nm, large Stokes shift (121 nm), excellent photostability, high water solubility, good cell permeability, and pH insensitivity in the biologically relevant range. The probe can selectively detect Hg2+ ions in live cells and living tissues without interference from other metal ions and the membrane-bound probes, and its quenching constant is 8.73 × 105 M–1.

Sign in / Sign up

Export Citation Format

Share Document