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1.
Carbohydr Polym ; 272: 118454, 2021 Nov 15.
Article in English | MEDLINE | ID: mdl-34420714

ABSTRACT

The development of robust solvent systems for cellulose dissolution is of significant importance for cellulose utilization and transformation. Herein, six kinds of novel superbase-based solvents were designed by a combination of 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) with pyridine N-oxide (PyO) or 2-picoline-N-oxide (PiO) for dissolution of cellulose. It was observed that the prepared superbase-based solvents (denoted as DBN-PyO-x and DBN-PiO-4) could efficiently dissolve cellulose at mild temperatures (<80 °C). The chemical structure of the prepared superbase-based solvents and the molar ratio of the components significantly affected the solubility of cellulose, and DBN-PyO-4 showed the best performance with a cellulose solubility of 14.1 wt% 70 °C. The systematic study revealed that the good performance of the prepared superbase-based solvents on cellulose dissolution resulted from the synergistic effect of their ability to form hydrogen bonds and their polarizability.


Subject(s)
Cellulose/chemistry , Solvents/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Hydrogen Bonding , Picolines/chemistry , Pyridines/chemistry , Solubility , Temperature , X-Ray Diffraction/methods
2.
Ultrason Sonochem ; 77: 105702, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34375945

ABSTRACT

2-picoline is a very important pyridine derivative with significant applications though it is also poisonous and harmful having considerable adverse influence on aquatic life, environment and organisms. The need for developing effective treatment methodologies for 2-Picoline directed the current work focusing on degradation of 2-Picoline using the combination of ultrasound and advanced oxidants such as hydrogen peroxide (H2O2), potassium persulphate (KPS), Fenton's reagent, and Peroxymonosulphate (PMS) along with the use of Titanium oxide (TiO2) as catalyst. Ultrasonic bath having 8 L capacity and operating frequency of 40 ± 2 kHz has been used. The effect of parameters like power, initial pH, temperature, time and initial concentration of 2-Picoline were studied to establish best operating conditions which were further used in the combination treatment approaches of ultrasound with oxidising agents. The chemical oxygen demand (COD) reduction for the optimized approaches of ultrasound in combination with oxidizing agents was also determined. Degradation experiments were performed using oxidising agents also in absence of ultrasound to investigate the individual treatment capacity of the oxidants and also the synergetic index for the combination. Kinetic study demonstrated that second order model suited for all the treatment approaches except US/Fenton where first order model fitted better. Ultrasound in combination with Fenton reagent demonstrated a substantial synergy for the degradation of 2-Picoline compared to other treatment approaches showing highest degradation of 97.6 %, synergetic index as 5.71, cavitational yield of 1.82 × 10-5 mg/J and COD removal of 82.4 %.


Subject(s)
Oxidants/chemistry , Picolines/chemistry , Ultrasonic Waves , Hydrogen-Ion Concentration , Kinetics , Temperature
3.
Macromol Biosci ; 21(6): e2100048, 2021 06.
Article in English | MEDLINE | ID: mdl-33861507

ABSTRACT

Zinc ion complexes of dipicolylamine analogs, due to the strong synergistic effect between the Zn2+ complex of containing polypyridine derivatives and polycations in each key step of pDNA transport, have been used as the third component to mediate polyethyleneimine with molecular weight 1.8 kDa (PEI1.8k)/DNA gene delivery system. And the effects of different structural characteristics, such as the number of pyridinamine ligands, the hydrophilic-hydrophobicity of the adjacent groups, on the in vitro transfection performance of the ternary complex are systematically investigated. This ternary hybrid system provides an effective strategy to improve the gene delivery of cationic polymers.


Subject(s)
DNA/metabolism , Gene Transfer Techniques , Organometallic Compounds/chemistry , Picolines/chemistry , Plasmids/metabolism , Polyethyleneimine/chemistry , Carbocyanines/chemistry , Cations , DNA/genetics , Fluorescein-5-isothiocyanate/chemistry , Fluorescent Dyes/chemistry , HEK293 Cells , Humans , Hydrophobic and Hydrophilic Interactions , Ligands , Molecular Weight , Organometallic Compounds/metabolism , Picolines/metabolism , Plasmids/chemistry
4.
Nat Commun ; 11(1): 6226, 2020 12 04.
Article in English | MEDLINE | ID: mdl-33277485

ABSTRACT

Protein N-phosphorylation plays a critical role in central metabolism and two/multicomponent signaling of prokaryotes. However, the current enrichment methods for O-phosphopeptides are not preferred for N-phosphopeptides due to the intrinsic lability of P-N bond under acidic conditions. Therefore, the effective N-phosphoproteome analysis remains challenging. Herein, bis(zinc(II)-dipicolylamine)-functionalized sub-2 µm core-shell silica microspheres (SiO2@DpaZn) are tailored for rapid and effective N-phosphopeptides enrichment. Due to the coordination of phosphate groups to Zn(II), N-phosphopeptides can be effectively captured under neutral conditions. Moreover, the method is successfully applied to an E.coli and HeLa N-phosphoproteome study. These results further broaden the range of methods for the discovery of N-phosphoproteins with significant biological functions.


Subject(s)
Microspheres , Organometallic Compounds/chemistry , Phosphoproteins/metabolism , Picolines/chemistry , Proteome/analysis , Proteomics/methods , Silicon Dioxide/chemistry , Escherichia coli Proteins/analysis , HeLa Cells , Hep G2 Cells , Humans , Neoplasm Proteins/analysis , Particle Size , Phosphopeptides/analysis , Reproducibility of Results , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods
5.
Molecules ; 25(3)2020 Feb 10.
Article in English | MEDLINE | ID: mdl-32050511

ABSTRACT

p-Coumaric acid (pCA) and trans-ferulic acid (TFA) were co-crystallised with 2-amino-4-picoline (2A4MP) and 2-amino-6-picoline (2A6MP) producing organic salts of (pCA-)(2A4MP+) (1), (pCA̶ )(2A6MP+) (2) and (TFA̶ )(2A4MP+)·( 3 2 H2O) (3). For salt 3, water was included in the crystal structure fulfilling a bridging role. pCA formed a 1:1 salt with 2A4MP (Z' = 1) and a 4:4 salt with 2A6MP (Z' = 4). The thermal stability of the salts was determined using differential scanning calorimetry (DSC). Salt 2 had the highest thermal stability followed by salt 1 and salt 3. The salts were also characterised using Fourier transform infrared (FTIR) spectroscopy. Hirshfeld surface analysis was used to study the different intermolecular interactions in the three salts. Solvent-assisted grinding was also investigated in attempts to reproduce the salts.


Subject(s)
Coumaric Acids/chemistry , Picolines/chemistry , Propionates/chemistry , Calorimetry, Differential Scanning , Crystallization , Crystallography, X-Ray , Hydrogen Bonding , Salts/chemistry , Solvents , Spectrophotometry, Infrared , Spectroscopy, Fourier Transform Infrared
6.
Org Lett ; 22(4): 1495-1498, 2020 02 21.
Article in English | MEDLINE | ID: mdl-32026682

ABSTRACT

A general method has been developed for the formation of glycosyl chlorides and bromides from picolinic esters under mild and neutral conditions. Benchtop stable picolinic esters are activated by a copper(II) halide species to afford the corresponding products in high yields with a traceless leaving group. Rare ß glycosyl chlorides are accessible via this route through neighboring group participation. Additionally, glycosyl chlorides with labile protecting groups previously not easily accessible can be prepared.


Subject(s)
Bromides/chemical synthesis , Chelating Agents/chemistry , Chlorides/chemical synthesis , Esters/chemistry , Glycosides/chemical synthesis , Picolines/chemistry , Bromides/chemistry , Chlorides/chemistry , Glycosides/chemistry , Molecular Structure
7.
Bull Exp Biol Med ; 167(6): 744-746, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31655995

ABSTRACT

We studied membranotropic properties of NO donor 2-nitroxysuccinate 3-hydroxy-6-methyl-2-ethylpyridine and its structural analog succinate 3-hydroxy-6-methyl-2-ethylpyridine (Mexidol). It was shown that the compounds under study are incorporated into modeled membranes and form long-living complexes with pyrene in the region of fatty acid tails of phospholipids. Luminol-amplified chemiluminescence analysis showed that both compounds exhibited antiradical activity and in a concentration of 0.1 mM reduced chemiluminescence intensity by more than 70%. 2-Nitroxysuccinate 3-hydroxy-6-methyl-2-ethylpyridine inhibited catalytic activity of monoamine oxidase A more efficiently than its structural analogue Mexidol.


Subject(s)
Antioxidants/pharmacology , Cell Membrane/drug effects , Free Radicals/metabolism , Lipid Peroxidation/drug effects , Animals , Cell Membrane/enzymology , Cell Membrane/metabolism , Heart , Liposomes/chemistry , Luminescent Measurements , Male , Mice , Mice, Inbred C57BL , Monoamine Oxidase/drug effects , Monoamine Oxidase/metabolism , Myocardium/chemistry , Myocardium/metabolism , Phosphatidylcholines/chemistry , Phosphatidylcholines/metabolism , Picolines/chemistry , Picolines/pharmacology
8.
J Med Chem ; 62(13): 6047-6062, 2019 07 11.
Article in English | MEDLINE | ID: mdl-31181158

ABSTRACT

We report that compound 13, a novel phosphatidylserine-targeting zinc(II) dipicolylamine drug conjugate, readily triggers a positive feedback therapeutic loop through the in situ generation of phosphatidylserine in the tumor microenvironment. Linker modifications, pharmacokinetics profiling, in vivo antitumor studies, and micro-Western array of treated-tumor tissues were employed to show that this class of conjugates induced regeneration of apoptotic signals, which facilitated subsequent recruitment of the circulating conjugates through the zinc(II) dipicolylamine-phosphatidylserine association and resulted in compounding antitumor efficacy. Compared to the marketed compound 17, compound 13 not only induced regressions in colorectal and pancreatic tumor models, it also exhibited at least 5-fold enhancement in antitumor efficacy with only 40% of the drug employed during treatment, culminating in a >12.5-fold increase in therapeutic potential. Our study discloses a chemically distinct apoptosis-targeting theranostic, with built-in complementary functional moieties between the targeting module and the drug mechanism to expand the arsenal of antitumor therapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Coordination Complexes/therapeutic use , Indolizines/therapeutic use , Neoplasms/drug therapy , Phosphatidylserines/metabolism , Picolines/therapeutic use , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Drug Design , Humans , Indolizines/chemical synthesis , Indolizines/chemistry , Male , Mice, Inbred ICR , Mice, Nude , Molecular Structure , Picolines/chemical synthesis , Picolines/chemistry , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/therapeutic use , Xenograft Model Antitumor Assays , Zinc/chemistry
9.
Arch Pharm (Weinheim) ; 352(6): e1900007, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31066105

ABSTRACT

Niflumic acid is used to treat inflammatory rheumatoid diseases, pain, and fever. The present study reports the experimental, spectroscopic, thermal, structural analyses, and biological activities of this complex. The nonsteroidal anti-inflammatory drug niflumic acid, 3-picoline, and copper(II) chloride were utilized to synthesize a new complex: [Cu2 Cl 2 (nif) 2 (3-pic) 4 ]. The crystal structure of [Cu 2 Cl 2 (nif) 2 (3-pic) 4 ] was determined by X-ray crystallography. The complex crystallizes in the triclinic space group P-1 and each Cu(II) center displayed six-coordinated distorted octahedral geometry. Two Cu(II) centers are connected by a chloro-bridge to form the binuclear metal core. Finally, the in vitro effects of the synthesized new complex and free niflumic acid were evaluated on the human serum paraoxonase 1 enzyme. At low doses, both the new complex and free niflumic acid showed very good inhibition activity with different inhibition mechanisms. In addition, the results showed that the new complex has more inhibition activity than free niflumic acid.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Aryldialkylphosphatase/antagonists & inhibitors , Coordination Complexes/chemical synthesis , Copper/chemistry , Niflumic Acid/chemistry , Picolines/chemistry , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , Crystallography, X-Ray , Humans , Models, Molecular , Molecular Structure
10.
Scand J Clin Lab Invest ; 79(1-2): 17-24, 2019.
Article in English | MEDLINE | ID: mdl-30880483

ABSTRACT

This study was targeted on a metabolomic approach to compare the blood serum free amino acid profiles and concentration of confirmed breast cancer (stages I-III) patients to healthy controls in order to establish reliable biomarkers of early detection and prediction of breast cancer. The ultra-high-performance liquid chromatography coupled with mass spectrometry using positive ionization electrospray was applied for the picoline-derivatized serum free amino acids using the EZ:faastTM kit. Multivariate statistical analysis principal component analysis, partial least squares discrimination analysis and univariate analysis were applied in order to discriminate between patient groups and putative amino acid biomarkers for breast cancer. A significant decrease of amino acid concentrations between the breast cancer group and the control group was positively correlated with breast cancer progression. Arginine, Alanine, Isoleucine, Tyrosine and Tryptophan were identified as being good potential discriminants (AUROC ≥0.85) and suitable candidates to diagnose and predict the breast cancer progression.


Subject(s)
Amino Acids/blood , Biomarkers, Tumor/blood , Breast Neoplasms/diagnosis , Early Detection of Cancer/methods , Metabolome , Adult , Aged , Breast Neoplasms/blood , Breast Neoplasms/pathology , Case-Control Studies , Chromatography, High Pressure Liquid/methods , Disease Progression , Female , Humans , Metabolomics/methods , Middle Aged , Multivariate Analysis , Neoplasm Staging , Picolines/chemistry , Principal Component Analysis , Spectrometry, Mass, Electrospray Ionization
11.
Biotechniques ; 66(3): 135-142, 2019 03.
Article in English | MEDLINE | ID: mdl-30869547

ABSTRACT

An electrochemical approach was devised for detecting DNA damage and differentiating two DNA damage mechanisms, which is important to the design of new chemotherapeutics. This approach combined two platforms, based on the detection of base damage and DNA strand cleavage. In this work, our approach was demonstrated for the detection of cisplatin-induced DNA damage and the enhancement effects of two electron donors, N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) and reduced graphene oxide (rGO). Our results demonstrated that TMPD enhanced DNA strand cleavage, supporting the proposed dissociative electron transfer mechanism. While rGO, which is an efficient electron donor, failed to show any enhancement (suggesting the lack of free-radical generation), overall, this electrochemical approach could be implemented for discovering next-generation DNA damage-based chemotherapy drugs.


Subject(s)
Biosensing Techniques , DNA Damage/drug effects , Electrochemical Techniques , Cisplatin/adverse effects , Cisplatin/therapeutic use , Drug Therapy, Combination/adverse effects , Graphite/chemistry , Humans , Picolines/chemistry
12.
Ann Nucl Med ; 33(5): 317-325, 2019 May.
Article in English | MEDLINE | ID: mdl-30726551

ABSTRACT

PURPOSE: Although it has been traditionally surmised that phosphatidylserine (PS) externalization is a hallmark of apoptosis, most other non-apoptotic modes of cell death, such as necrosis, are also associated with PS externalization. Bis(zinc-dipicolylamine) (ZnDPA) complexes have been reported to exhibit affinity for PS. The present study aimed to develop novel radiolabeled ZnDPA derivatives for cell death imaging in tumor after treatment with anticancer drugs. METHODS: [125I]IB-EG2-ZnDPA and [99mTc]Tc-MAG3-EG2-ZnDPA were designed and prepared. The stabilities of these radiotracers were determined in 0.1 M phosphate buffer (pH 7.4) or murine plasma at 37 °C, and their 1-octanol/water partition coefficients (logP) were measured. The uptake of radioactivity in cancer cells, which were preincubated in a normal medium or in a medium containing 5-FU, was measured after incubation with radiotracers. Accumulation of [99mTc]Tc-MAG3-EG2-ZnDPA in the tumor was evaluated in tumor-bearing mice treated with or without 5-FU, and then TUNEL staining was performed to detect dead cells in the tumor tissue sections. RESULTS: The radiochemical purities of [125I]IB-EG2-ZnDPA and [99mTc]Tc-MAG3-EG2-ZnDPA exceeded 95%. Although [125I]IB-EG2-ZnDPA gradually decomposing with time, more than 90% of [99mTc]Tc-MAG3-EG2-ZnDPA remained in its intact form in phosphate buffer through 6 h of incubation. Neither [125I]IB-EG2-ZnDPA nor [99mTc]Tc-MAG3-EG2-ZnDPA decomposed so much after 6-h incubation in murine plasma. [125I]IB-EG2-ZnDPA could not specifically recognize PS on the cell surface because of its high lipophilicity. Conversely, [99mTc]Tc-MAG3-EG2-ZnDPA accumulated in cancer cells after treatment with an anticancer drug both in vitro and in vivo, and its accumulation was correlated with the number of TUNEL-positive cells. However, the biodistribution of [99mTc]Tc-MAG3-EG2-ZnDPA was not suitable for imaging because of its low accumulation in tumor and high uptake in abdomen organs. CONCLUSION: [99mTc]Tc-MAG3-EG2-ZnDPA could be useful for the early detection of treatment effects after chemotherapy. Since the signal-to-noise ratio is not enough for single photon emission computed tomography imaging, further modification is needed to improve its biodistribution and affinity for PS.


Subject(s)
Molecular Imaging/methods , Organometallic Compounds/chemistry , Picolines/chemistry , Animals , Biological Transport , Cell Death/drug effects , Cell Line, Tumor , Female , Fluorouracil/chemistry , Fluorouracil/pharmacology , Humans , Iodine Radioisotopes/chemistry , Isotope Labeling , Mice , Organometallic Compounds/metabolism , Organometallic Compounds/pharmacokinetics , Picolines/metabolism , Picolines/pharmacokinetics , Radiochemistry , Tissue Distribution
13.
Molecules ; 23(12)2018 Dec 11.
Article in English | MEDLINE | ID: mdl-30544920

ABSTRACT

The corrosion inhibition performance of pyridine derivatives (4-methylpyridine and its quaternary ammonium salts) and sulfur-containing compounds (thiourea and mercaptoethanol) with different molar ratios on carbon steel in CO2-saturated 3.5 wt.% NaCl solution was investigated by weight loss, potentiodynamic polarization, electrochemical impedance spectroscopy, and scanning electron microscopy. The synergistic corrosion inhibition mechanism of mixed inhibitors was elucidated by the theoretical calculation and simulation. The molecules of pyridine derivative compounds with a larger volume has priority to adsorb on the metal surface, while the molecules of sulfur-containing compounds with a smaller volume fill in vacancies. A dense adsorption film would be formed when 4-PQ and sulfur-containing compounds are added at a proper mole ratio.


Subject(s)
Carbon Dioxide/chemistry , Mercaptoethanol/chemistry , Picolines/chemistry , Sodium Chloride/chemistry , Steel/chemistry , Thiourea/chemistry , Corrosion , Quaternary Ammonium Compounds/chemistry , Solutions
14.
Acta Crystallogr C Struct Chem ; 74(Pt 7): 797-806, 2018 07 01.
Article in English | MEDLINE | ID: mdl-29973419

ABSTRACT

New salt forms of the antioxidant drug emoxypine (EMX, 2-ethyl-6-methylpyridin-3-ol) with pharmaceutically acceptable maleic (Mlt), malonic (Mln) and adipic (Adp) acids were obtained {emoxypinium maleate, C8H12NO+·C4H3O4-, [EMX+Mlt], emoxypinium malonate, C8H12NO+·C3H3O4-, [EMX+Mln], and emoxypinium adipate, C8H12NO+·C6H9O4-, [EMX+Adp]} and their crystal structures determined. The molecular packing in the three EMX salts was studied by means of solid-state density functional theory (DFT), followed by QTAIMC (quantum theory of atoms in molecules and crystals) analysis. It was found that the major contribution to the packing energy comes from pyridine-carboxylate and hydroxy-carboxylate heterosynthons forming infinite one-dimensional ribbons, with [EMX+Adp] additionally stabilized by hydrogen-bonded C(9) chains of Adp- ions. The melting processes of the [EMX+Mlt] (1:1), [EMX+Mln] (1:1) and [EMX+Adp] (1:1) salts were studied and the fusion enthalpy was found to increase with the increase of the calculated lattice energy. The dissolution process of the EMX salts in buffer (pH 7.4) was also studied. It was found that the formation of binary crystals of EMX with dicarboxylic acids increases the EMX solubility by more than 30 times compared to its pure form.


Subject(s)
Adipates/chemistry , Dicarboxylic Acids/pharmacology , Ions/chemistry , Maleates/chemistry , Picolines/pharmacology , Pyridines/pharmacology , Crystallography, X-Ray , Dicarboxylic Acids/chemistry , Hydrogen Bonding , Picolines/chemistry , Pyridines/chemistry , Solubility
15.
Adv Healthc Mater ; 7(14): e1800296, 2018 07.
Article in English | MEDLINE | ID: mdl-29745029

ABSTRACT

Nanomedicine has significantly impacted cancer theranostics. However, its efficiency is restricted by the limited enhanced permeability and retention effect of nanomaterials and insufficient density/specificity of receptors of tumor cells. Herein, an apoptosis-homing nanoplatform based on zinc(II) dipicolylamine (ZnDPA) conjugated Fe/Fe3 O4 nanoparticles (MNPs/ZnDPA), which demonstrates amplified magnetic resonance signal and photothermal therapy, is developed. In an apoptotic xenograft model constructed by doxorubicin, due to the high affinity between ZnDPA and the upregulated level of phosphatidylserine on the outer surface of apoptotic cancer cells, the accumulation value of MNPs/ZnDPA is enhanced two-fold and the tumor/muscle ratio of T2 values is decreased to 50% compared to that in the normal xenograft model. In the apoptotic xenograft model, the amplifying photothermal therapy is confirmed by the changes of the relative tumor volume and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining. This nanoplatform provides a promising strategy to improve the targeting efficiency of nanoparticles and the enhancement of tumor-targeting theranostics.


Subject(s)
Theranostic Nanomedicine/methods , Animals , Apoptosis/genetics , Apoptosis/physiology , Cell Line, Tumor , Doxorubicin/chemistry , Doxorubicin/therapeutic use , Female , Human Umbilical Vein Endothelial Cells , Humans , Magnetite Nanoparticles/chemistry , Mammary Neoplasms, Animal/drug therapy , Mice , Mice, Inbred BALB C , Organometallic Compounds/chemistry , Picolines/chemistry
16.
Int J Pharm ; 547(1-2): 169-180, 2018 Aug 25.
Article in English | MEDLINE | ID: mdl-29782971

ABSTRACT

In contact-less printing, such as piezo-electric drop on demand printing used in the study, the drop formation process is independent of the substrate. This means that having developed a printable formulation, printed pharmaceutical dosage forms can be obtained on any pharmaceutical grade substrate, such as polymer-based films. In this work we evaluated eight different oral films based on their suitability as printing substrates for sodium picosulfate. The different polymer films were compared regarding printed spot morphology, chemical stability and dissolution profile. The morphology of printed sodium picosulfate was investigated with scanning electron microscopy and optical coherence tomography. The spreading of the deposited drops was found to be governed by the contact angle of the ink with the substrate. The form of the sodium picosulfate drops changed on microcrystalline cellulose films at ambient conditions over 8 weeks and stayed unchanged on other tested substrates. Sodium picosulfate remained amorphous on all substrates according to small and wide angle X-ray scattering, differential scanning calorimetry and polarized light microscopy measurements. The absence of chemical interactions between the drug and substrates, as indicated by infrared spectroscopy, makes all tested substrates suitable for printing sodium picosulfate onto them.


Subject(s)
Drug Compounding/methods , Drug Delivery Systems , Printing , Administration, Oral , Cellulose/chemistry , Citrates/chemistry , Drug Liberation , Gelatin/chemistry , Hypromellose Derivatives/chemistry , Organometallic Compounds/chemistry , Picolines/chemistry , Titanium/chemistry , Wettability
17.
Inorg Chem ; 57(5): 2365-2368, 2018 Mar 05.
Article in English | MEDLINE | ID: mdl-29431435

ABSTRACT

We synthesized a new ratiometric fluorescent Cu2+ probe, bearing a morpholine moiety for selective binding to lysosomes and two picolylamine arms for the specific chelation of divalent copper ions. The probe capability to detect lysosomal Cu2+ was demonstrated in human differentiated neuroblastoma cells by confocal microscopy.


Subject(s)
Chelating Agents/chemistry , Copper/chemistry , Fluorescent Dyes/chemistry , Lysosomes/chemistry , Neuroblastoma/pathology , Optical Imaging , Cell Differentiation , Chelating Agents/chemical synthesis , Fluorescent Dyes/chemical synthesis , Humans , Microscopy, Confocal , Morpholines/chemistry , Picolines/chemistry
18.
Molecules ; 23(1)2018 Jan 20.
Article in English | MEDLINE | ID: mdl-29361698

ABSTRACT

An alternative strategy for the synthesis of 1-aryl- and 1-alkyl-2-methylsulfanyl-4-(4-fluorophenyl)-5-(pyridin-4-yl)imidazoles as potential p38α mitogen-activated protein kinase inhibitors is reported. The regioselective N-substitution of the imidazole ring was achieved by treatment of α-aminoketones with different aryl or alkyl isothiocyanates. In contrast to previously published synthesis routes starting from 2-amino-4-methylpyridine, the presented route is characterized by a higher flexibility and a lower number of steps. This strategy was also applied to access 1-alkyl-2-methylsulfanyl-5-(4-fluorophenyl)-4-(pyridin-4-yl)imidazoles in six steps starting from 2-chloro-4-methylpyridine.


Subject(s)
Imidazoles/chemical synthesis , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Isothiocyanates/chemistry , Ketones/chemistry , Picolines/chemistry , Stereoisomerism
19.
Eur J Med Chem ; 143: 1039-1052, 2018 Jan 01.
Article in English | MEDLINE | ID: mdl-29232581

ABSTRACT

Two series of homoleptic Pt(II)(hydrazone)Cl (C1a-C5a) and heteroleptic Pt(II)(hydrazone)(4-picoline). BF4 (C1b-C5b) complexes were prepared and characterized by 1H, 13C, 19F NMR and HR ESI-MS. Structure of C2b was confirmed by single crystal X-ray analysis. These complexes were studied for their in vitro anticancer activities in human multiple cancer cells including breast (MCF-7), liver (HepG2), lung (H460), colon (HCT116) and cervical (Hela) cancers. C1a-C5a and C1b-C5b showed considerable anticancer effect. The overall anticancer effect of all these complexes was higher in liver (HepG2) and lung (H460) cancer cell lines and the effect of C2b and C3b was observed to be the highest among these 10 complexes. Therefore, we selected C2b and C3b to study their in vitro anticancer mechanism in HepG2 and H460 cancer cells. C2b and C3b changed cancer cell morphology and inhibited cell migration. The anticancer mechanistic studies demonstrated that C2b and C3b induced cell apoptosis, as evidenced by DAPI and AO/EB staining and flow cytometry analyses. Moreover, qRT-PCR and western blotting analysis showed that H460 and HepG2 cells treated with C2b and C3b significantly increased the expression of p53, p63, p21, p15, Bax and decreased Bcl-2 and c-Myc levels. The DNA binding property of these complexes was investigated by gel electrophoresis using pBR322 plasmid DNA. Taken together, the results obtained from the present study demonstrated the potentials of this new class of Pt(II) complexes in reduction of cell viability, suppression of cell migration and acceleration of apoptosis in different cancer cells.


Subject(s)
Antineoplastic Agents/pharmacology , Hydrazones/pharmacology , Organoplatinum Compounds/pharmacology , Picolines/pharmacology , Platinum/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Hydrazones/chemistry , Molecular Structure , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Picolines/chemistry , Platinum/chemistry , Structure-Activity Relationship
20.
Bioorg Med Chem ; 25(20): 5820-5837, 2017 10 15.
Article in English | MEDLINE | ID: mdl-28943244

ABSTRACT

Picolinamide derivatives, linked to an arylpiperazine moiety, were prepared and their affinity to 5-HT1A, 5-HT2A and 5-HT2C receptors was evaluated. The combination of structural elements (heterocyclic nucleus, alkyl chain and 4-substituted piperazine), known to play critical roles in affinity for serotoninergic receptors, and the proper selection of substituents led to compounds with high specificity and affinity towards serotoninergic receptors. In binding studies, several molecules showed high affinity in nanomolar and subnanomolar range at 5-HT1A, 5-HT2A and 5-HT2C receptors and moderate or no affinity for other relevant receptors (D1, D2, α1 and α2). N-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl)picolinamide (3o) with Ki=0.046nM, was the most affine and selective derivative for the 5-HT1A receptor compared to other serotoninergic dopaminergic and adrenergic receptors. N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)picolinamide (3b), instead, showed a subnanomolar affinity towards 5-HT2A with Ki=0.0224nM, whereas N-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)ethyl)picolinamide (3s) presented an attractive 5-HT2C affinity with Ki=0.8nM. Moreover, the compounds having better affinity and selectivity binding profiles towards 5-HT2A were selected and tested on rat ileum, to determine their effect on 5HT induced contractions. Those more selective towards 5-HT1A receptors were studied in vivo on several behavioral tests.


Subject(s)
Ileum/drug effects , Picolines/chemical synthesis , Picolines/pharmacology , Receptor, Serotonin, 5-HT1A/metabolism , Receptor, Serotonin, 5-HT2A/metabolism , Receptor, Serotonin, 5-HT2C/metabolism , Animals , Binding Sites , Biological Assay , Ligands , Maze Learning/drug effects , Molecular Structure , Picolines/chemistry , Protein Binding/drug effects , Rats , Receptor, Serotonin, 5-HT1A/chemistry , Receptor, Serotonin, 5-HT2A/chemistry , Receptor, Serotonin, 5-HT2C/chemistry , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/pharmacology
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