Amino Derivatives Research Articles

Multiaction Pt(IV) Carbamate Complexes Can Codeliver Pt(II) Drugs and Amine Containing Bioactive Molecules.

Multiaction Pt(IV) prodrugs can overcome resistance associated with the FDA approved Pt(II) drugs like cisplatin. Intracellular reduction of the octahedral Pt(IV) derivatives of cisplatin releases cisplatin and the two axial ligands. When the released axial ligands act synergistically with cisplatin to kill the cancer cells, we have multiaction prodrugs. Most Pt(IV) multiaction prodrugs have bioactive ligands possessing a carboxylate that is conjugated to the Pt(IV) because breaking the Pt(IV)-ligand bond releases the active moiety. As many drugs that act synergistically with cisplatin do not have carboxylates, a major challenge is to prepare multiaction Pt(IV) complexes with drugs that have amino groups or hydroxyl groups such that following reduction, the drugs are released in their active form. Our objective was to prepare multiaction Pt(IV) prodrugs that release bioactive molecules having amino groups. Because we cannot conjugate amino groups to the axial position of Pt(IV), we developed a novel and efficient approach for the synthesis of Pt(IV)-carbamato complexes and demonstrated that following reduction of the Pt(IV), the released carbamates undergo rapid decarboxylation, releasing the free amine, as in the case of the PARP-1 inhibitor 3-aminobenzamide and the amino derivative of the HDAC inhibitor SAHA. Pt(IV)-carbamato complexes are stable in cell culture medium and are reduced by ascorbate. They are reduced slower than their carboxylato and carbonato analogues. We believe that this approach paves the way for preparing novel classes of multiaction Pt(IV) prodrugs with amino containing bioactive molecules that up to now were not accessible.

SYNTHESIS OF NOVEL AZIDES AND TRIAZOLES ON THE BASIS OF 1 Н -PYRAZOLE-3(5)-CARBOXYLIC ACIDS

The goal of this work was to obtain novel ligands based on 1 H -pyrazole-3(5)-carboxylic acids containing the triazole moiety at positions 3(5) or 4. Another goal was to study the possibility of joining pyrazole carboxylic acid fragments with various framework structures to create polychelated ligands that can be used in medicinal chemistry and metal complex catalysis. Methods have been developed for the synthesis of previously unknown N -unsubstituted 5- and 4-azido-1 H -pyrazole-3-carboxylic acids from the corresponding available amino derivatives in high yields. For the first time, the joining of bispidines to azoles was carried out using the copper-catalyzed [3+2] cycloaddition reaction. Authors: Aleksander I. Dalinger, Alexey V. Medved'ko, Alexandra I. Balalaeva, Irina А. Vatsadze, Igor L. Dalinger, Sergey Z. Vatsadze*

Exploring the nitro group reduction in low-solubility oligo-phenylenevinylene systems: Rapid synthesis of amino derivatives

A small series of amino oligo-phenylenevinylenes (OPVs) were successfully synthesized from their nitro-analogs in a rapid, simple, and highly efficient fashion employing a sodium sulfide/pyridine system as a reducing agent. In this research, classic and sustainable reduction methodologies including NH4HCO2/Zn and a choline chloride/tin (II) chloride deep eutectic solvent (DES) were also evaluated, showing degradation products, incomplete reactivity, and product isolation difficulties in all cases. The straightforward Na2S/pyridine synthetic protocol proved to maintain the E-E stereochemistry of the OPV backbone that has been previously assembled by the Mizoroki–Heck cross-coupling reaction. Also, the optoelectronic properties were determined and discussed, considering the amino group insertion in these conjugated systems as a contribution for future construction of novel materials with applications in supramolecular electronics, light harvesting, and photocatalysis.

Highly Fluorescent Distyrylnaphthalene Derivatives as a Tool for Visualization of Cellular Membranes.

Fluorescent imaging, which is an important interdisciplinary field bridging research from organic chemistry, biochemistry and cell biology has been applied for multi-dimensional detection, visualization and characterization of biological structures and processes. Especially valuable is the possibility to monitor cellular processes in real time using fluorescent probes. In this work, conjugated oligoelectrolytes and neutral derivatives with the distyrylnaphthalene core (SN-COEs) were designed, synthetized and tested for biological properties as membrane-specific fluorescent dyes for the visualization of membrane-dependent cellular processes. The group of tested compounds includes newly synthesized distyrylnaphthalene derivatives (DSNNs): a trimethylammonium derivative (DSNN-NMe3+), a phosphonate derivative (DSNN-P), a morpholine derivative (DSNN-Mor), a dihydroxyethylamine derivative (DSNN-DEA), a phosphonate potassium salt (DSNN-POK), an amino derivative (DSNN-NH2) and pyridinium derivative (DSNN-Py+). All compounds were tested for their biological properties, including cytotoxicity and staining efficiency towards mammalian cells. The fluorescence intensity of SN-COEs incorporated into cellular structures was analyzed by fluorescence activated cell sorting (FACS) and photoluminescence spectroscopy. The cytotoxicity results have shown that all tested SN-COEs can be safely used in the human and animal cell studies. Fluorescence and confocal microscopy observations confirm that tested COEs can be applied as fluorescent probes for the visualization of intracellular membrane components in a wide range of different cell types, including adherent and suspension cells. The staining procedure may be performed under both serum free and complete medium conditions. The presented studies have revealed the interesting biological properties of SN-COEs and confirmed their applicability as dyes for staining the membranous structures of eukaryotic cells, which may be useful for visualization of wide range of biological processes dependent of the extra-/intracellular communications and/or based on the remodeling of cellular membranes.

Synthesis of Novel Azides and Triazoles on the Basis of 1н-Pyrazole-3(5)-Carboxylic Acids

The goal of this work was to obtain novel ligands basedis on 1H-pyrazole-3(5)-carboxylic acids containing the triazole moiety at positions 3(6) or 4. Another goal was to study the possibility of joining pyrazole carboxylic acid fragments with various framework structures to create polychelated ligands that can be used in medicinal chemistry and metal complex catalysis. Methods have been developed for the synthesis of previously unknown N-unsubstituted 5- and 4-azido-1H-pyrazole-3-carboxylic acids from the corresponding available amino derivatives in high yields. For the first time, the joining of bispidines to azoles was carried out using the copper-catalyzed [3+2] cycloaddition reaction.

A practical synthesis of amino limonin/deoxylimonin derivatives as effective mitigators against inflammation and nociception.

A practical synthetic route, consisting of 5 steps, has been developed and applied successfully for converting limonin/deoxylimonin into the corresponding amino derivatives I- 5a-I- 5e and II- 5a-II- 5e. Deoxylimonin analogs II- 5a and II- 5b bearing an open A ring structure underwent ring closure reaction by employing the Mitsunobu procedure to afford II- 6a and II- 6b. All of the 12 newly synthesized compounds were subjected to preliminary screening for evaluating their inflammation and nociception inhibition efficacy. The most promising compounds, I- 5b and II- 5d, were selected for further investigation by a carrageenan-induced mouse paw edema model, both of which displayed a dose-response dependent manner and demonstrated superior anti inflammation capacity to that of indomethacin in the first 2 hours.

DFT evaluation of the effects of OH, NH2 and Br substituents on the properties of 2,2′-bipyridine derivatives

A theoretical assessment of the effects of the OH, NH2 and Br substituents on the properties of 2,2′-bipyridine has been carried out using density functional theory approach. The substituents were found to alter both electronic and structural properties of substituted 2,2′-bipyridine with the inductive and resonance effects playing significant roles. For the relative stability study, an order of ortho > para > meta was predicted for each set of the 2,2′-bipyridine derivatives with the ortho conformers being more stable by 4.62, 6.54 and 2.18 kcal/mol than the meta counterparts of the hydroxo, amino and bromo configurations respectively. On the part of electronic property, the electron donating / withdrawing tendency of the substituents was crucial in making electrons available to the bipyridine system. A general reduction in HOMO – LUMO energy gap was noticed upon substitution with the NH2 substituent having greater effect. Furthermore, the calculated reactivity parameters of the 2,2′-bipyridine were altered by substitution with –OH and –NH2 substituents causing reduction in ionization potential (IP) and absolute electronegativity (χ) while the –Br substituent did otherwise. For the solubility simulation, a more negative ΔGsolution was predicted for the hydroxo and amino derivatives at the para position, but reverse was the case for the bromo counterpart. In the case of the optical property, the range separated Time-dependent (LC-TDDFT) calculation revealed that the shifts in absorption λmax caused by the substitution is both substituent and position dependent.

Dietary supplementation with N-carbamylglycinate (CGly) improved feed source proline absorption and reproductive performance in sows.

Nutrient requirements are increased in the late-gestation period due to the faster growth of the foetal-placental unit and maternal erythrocyte mass. Glycine, proline and arginine are important amino acids that could improve foetal growth and development. The present study aims to investigate the effects of a derivative of glycine (N-carbamylglycinate, CGly) on the amino acid profiles and reproductive performances of late gestation sows. Thirty-two multiparous gestating sows (∼d 80) were selected, and randomly assigned into two groups: (1) control and (2) treatment (CGly, 800 mg kg-1) from day 85 of gestation to parturition. The serum amino acid profiles at day 110 of gestation and reproductive performance were investigated. The results showed that dietary supplementation of CGly in the late gestation period significantly improved the levels of glycine (p < 0.05) and proline (p < 0.01) in the serum of the perinatal sows, and thereafter improved the litter birth weights (p < 0.05) and number born alive (p < 0.1). Based on the in vitro studies, the improvement of proline levels is probably due to the induced expression of SLC6A20 and SLC38A2. Further studies should focus on the details of amino acid absorption, especially the competitive and cooperative absorption processes for different amino acids and derivatives.

Сополимеризация бутадиена-1,3 и стирола в присутствии инициаторов на основе аминопроизводных винилбензилхлорида

Сополимеризация бутадиена-1,3 и стирола в присутствии инициаторов на основе аминопроизводных винилбензилхлорида

Alkaline earth-organic frameworks with amino derivatives of 2,6-naphthalene dicarboxylates: structural studies and fluorescence properties.

Alkaline earth metal ion organic frameworks (AEMOFs) represent a relatively underexplored subcategory of metal-organic frameworks (MOFs). In this contribution, we present the synthesis and structural study of the new MOFs 1-8 based on the alkaline earth ions Mg2+, Ca2+, Sr2+ and Ba2+ and the amino substituted bridging ligands 4-aminonaphthalene-2,6-dicarboxylate (ANDC2-) and 4,8-diaminonaphthalene-2,6-dicarboxylate (DANDC2-). Compounds 1, 5, 6, 7 and 8 constitute rare examples of three-dimensional MOFs which feature square planar M4 secondary building units (SBUs) surrounded by eight bridging ditopic ligands. The underlying topology of MOFs 1, 5, 7 and 8 conforms to the 4-c pcb net which can be simplified to the 8-c bcu net, while 6 adopts the 4-c lta net which simplifies to the 8-c reo net. To the best of our knowledge these are the first examples of MOFs of their structural types formed by linear dicarboxylates instead of trigonal tricarboxylates or tetrahedral tetracarboxylates. Compounds 2, 3 and 4 also feature three dimensional networks with linear rod-shaped SBUs with the Ba2+ MOF 3 displaying an sra rod-net and MOFs 2 and 4 showing very complex rod-nets with so far unique topologies. Fluorescence studies revealed that the free ligands exhibit strong blue-green emission displaying considerable positive solvatochromism thereby pointing towards charge transfer excited states involving the shift of electron density from the amino groups to the aromatic core. Correspondingly, the MOFs display ligand based fluorescence with small differences in emission maxima possibly attributable to the difference in the charge density of the metal ions combined with the different environments around ligands in the crystal structures.

Synthesis, Reactions, and Antimicrobial Activity of Novel Heterocyclic Compounds Containing Cyclopenta[d]thieno[2,3-b]pyridine Moiety and Related Fused Heterocycles

We describe a simple method to synthesize novel 4-cyano-1-morpholin-4-yl-6,7-dihydro-5H-cyclopenta[c]pyridine-3-thione by the reaction of 3-amino-1-thioxo-1,5,6,7-tetrahydrocyclopenta[c]thiopyran-4-carbonitrile with morpholine through Dimroth rearrangement. The 1-amino-5-morpholin-4-yl-7,8-dihydro-6H-cyclopenta[d]thieno[2,3-b]pyridine-2-carboxamide, which was synthesized by two methods, was used as a versatile precursor for synthesis of new thienopyrimidines fused to cyclopenta[d]pyridine ring system. Consequently, reaction of the amino-carboxamide with diethylmalonate, triethyl orthoformate, and cycloalkanones afforded the corresponding fused pyrimidine heterocycles. On the other hand, chloroacetylation of the amino-carboxamide using chloroacetyl chloride in dioxane produced the chloroacetyl amino derivative that in turn underwent cyclocondensation upon reaction with acetic anhydride to give the chloromethyl pyrimidinone. The latter compound was subjected to react with various nitrogen nucleophiles by nucleophilic substitution reactions to yield the akyl (aryl)amino methyl pyrimidinones. Subsequently, treatment of the phenyl aminomethyl derivative with formaldehyde under Mannich conditions produced the imidazopyridothienopyrimidine ring system. Similarly, reaction of the phenyl aminomethyl pyrimidonone with chloroacetyl chloride afforded a new heterocyclic system namely, cyclopentapyridothienopyrimidopyrazine. On the other hand, reaction of the amino-carboxamide with carbon disulfide in pyridine led to the formation of oxopyrimidine thione, which was alkylated by the reaction with different α-halo carbonyl compounds. The newly synthesized compounds were fully characterized on the basis of elemental and spectral analyses. Alternatively, some of these compounds revealed promising antibacterial and antifungal activities through the in vitro screening.

Aqueous fullerene C60 solution suppresses herpes simplex virus and cytomegalovirus infections

Fullerene C60 is known as a promising therapeutic agent due to its antioxidant, anti-inflammatory and other properties, along with the lack of noticeable toxicity. In this article, we describe antiviral properties of aqueous fullerene C60 dispersion (ndC60) produced by biocompatible diafiltration technology and C60 amino derivatives against Herpes simplex virus type 1 (HSV-1) and Human cytomegalovirus (HCMV) infections. Their activity in vitro was evaluated by a plaque reduction assay using Vero and HF cells in pre- and post-treatment modes. Therapeutic efficacy of dnC60 and C60 derivatives was studied in DBA mice using cutaneous model of HSV-1 infection. Data obtained indicated low cytotoxicity of all used compounds for both cell lines (CC50 > 1 mg/ml). The antiviral activity of dnC60 in most tests exceeded the activity of both C60 amino adducts and acyclovir (ACV), and it demonstrated significant therapeutic effect against HSV-1 skin infection in mice.

Primary screening of the biological activity of heterocyclic aminoderivatives of 2,3-dichloro-1,4-naphtoquinone

The aim. Check the antimicrobial and fungicidal activity of 2,3-dichloro-1,4-naphthoquinone aminopyrazole derivatives and predict their severity of toxicity to rats.Materials and methods of the research. The antimicrobial activity of heterocyclic amino derivatives of naphthoquinone 3a-d was studied by diffusion of the substance into agar on solid nutrient medium and by serial dilution. Acute rodent toxicity was determined by the QSAR simulation method implemented in GUSAR software.Results. In the work, the antimicrobial and fungicidal activities of new heterocyclic amino derivatives of naphthoquinone were studied, as well as the in silico determination of their acute toxicity for rats was carried out using four types of substance administration.Conclusions. The study of aminopyrazole derivatives of naphthoquinone revealed the compounds exhibiting high antimicrobial activity against the Candida tenuis test culture, namely: 2-chloro-3-((1-methyl-1H-pyrazol-4-yl) amino) naphthalene-1,4-dione (3a) and 2-chloro-3 - ((1-methyl-1H-pyrazol-3-yl) amino) naphthalene-1,4-dione (3b). All the synthesized compounds were found to exhibit selective bacterio- and fungistatic activity. QSAR determined the non-toxic compound 3c in the intraperitoneal route of administration, as well as the non-toxic compound 3d in the subcutaneous route of administration

Functionalization of 3‐Iodo‐N,N‐Diisopropylferrocene‐Carboxamide, a Pivotal Substrate to Open the Chemical Space to 1,3‐Disubstituted Ferrocenes

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Amino Acid and Polyamine Membrane Transporters in Trypanosoma cruzi: Biological Function and Evaluation as Drug Targets.

Amino acids and polyamines are involved in relevant processes for the parasite Trypanosoma cruzi, like protein synthesis, stress resistance, life cycle progression, infection establishment and redox balance, among others. In addition to the biosynthetic routes of amino acids, T. cruzi possesses transport systems that allow the active uptake from the extracellular medium; and in the case of polyamines, the uptake is the unique way to obtain these compounds. The TcAAAP protein family is absent in mammals and its members are responsible for amino acid and derivative uptake, thus the TcAAAP permeases are not only interesting and promising therapeutic targets but could also be used to direct the entry of toxic compounds into the parasite. Although there is a treatment available for Chagas disease, its limited efficacy in the chronic stage of the disease, as well as the side effects reported, highlight the urgent need to develop new therapies. Discovery of new drugs is a slow and cost-consuming process, and even during clinical trials the drugs can fail. In this context, drug repositioning is an interesting and recommended strategy by the World Health Organization since costs and time are significantly reduced. In this article, amino acids and polyamines transport and their potential as therapeutic targets will be revised, including examples of synthetic drugs and drug repurposing.

A gas chromatography-mass spectrometry (GC-MS) metabolomic approach in human colorectal cancer (CRC): the emerging role of monosaccharides and amino acids.

Colorectal cancer (CRC) has been confirmed to be the third most commonly diagnosed cancer in males and the second in females. We investigated the blood plasma metabolome in CRC patients and in healthy adults to elucidate the role of monosaccharides, amino acids, and their respective metabolic pathways as prognostic factors in patients with CRC. Fifteen patients with CRC and nine healthy adults were enrolled in the study and their blood plasma samples analyzed by gas chromatography-mass spectrometry (GC-MS). Univariate Student's t-test, multivariate principal component analysis (PCA) and partial least square-discriminant analysis (PLS-DA) were conducted on MetaboAnalyst 4.0. The analysis of metabolic profiles was carried out by the web-based extension Metabolite Sets Enrichment Analysis (MSEA). Overall, 125 metabolites were identified in plasma samples by GC-MS. In CRC patient samples, nine metabolites, including D-mannose and fructose, were significantly more abundant than in controls; conversely, eleven amino derivatives were less abundant, including methionine, valine, lysine, and proline. Methionine was significantly less abundant in died patients compared with survivors. The most significantly altered metabolic pathways in CRC patients are those involving monosaccharides (primarily the catabolic pathway of fructose and D-mannose), and amino acids (primarily methionine, valine, leucine, and isoleucine). The abundance of D-mannose in CRC patient samples contributes to inhibiting the growth of cancer cells, while the abundance of fructose may be consistent either with low consumption of fructose by aerobic glycolysis within cancer cells or with a high bioavailability of fructose from diet. The reduction in methionine concentration may be related to increased activity of the threonine and methionine catabolic pathways, confirmed by high levels of α-hydroxybutyrate.

Влияние природы растворителя на физико-химические характеристики производных хинолина

The influence of the solvent nature on some physicochemical parameters of the quinoline derivatives molecules is investigated. It was noted that a variety of intermolecular interactions arising between the dissolved substance and the solvent and often accompanied by the phenomena of solvation, association, etc. leads to a variety of structural and energy changes in such systems and complicating their description. The most urgent problems of solutions include issues related to the solubility and bioavailability of biologically active compounds and drugs, the study of their ability to dissolve, the permeability of biological barriers, targeted delivery, etc., as well as the problems associated with the study of sorption of organic compounds from aqueous-organic eluents, for example, in liquid chromatography. Derivatives of quinoline (4-carboxy- and 4-aminoquinoline), known as potential drugs with various types of pharmacological action, were used as research objects. Using quantum chemical calculations, the dipole moment of the amino and carboxy derivatives of quinoline was determined, and the data obtained for vacuum and in solvents of various chemical nature were compared. A significant effect of solvent polarity on the dipole moment of quinoline derivatives dissolved in these solvents was found. The values of the solvation energy of quinoline derivatives in solvents of various chemical nature are calculated. It is shown that a change in the solvation energy is determined both by the structure of the molecules of the quinoline derivatives and by the polarity of the solvent. A nonlinear change in the energy of solvation with a change in the polarity of the solvent is established. A comparison is made of the values of the quinoline derivatives molecules polar surface area in solvents of various chemical nature. It was found that the polar surface area of the studied compounds changes slightly with a change in the nature of the solvent.

GC-MS and LC-MS analyses reveal the distribution of primary and secondary metabolites in mangosteen (Garcinia mangostana Linn.) fruit during ripening

Mangosteen (Garcinia mangostana Linn.) is a functional fruit rich in highly beneficial metabolites, particularly xanthones, which exhibit various bioactive properties, including antioxidant and anti-inflammatory activities. Given its pharmaceutical benefits, the market demand for mangosteen is continuing to increase; however, little is known about the metabolic changes that occur during ripening. Here we used a combination of gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-MS (LC-MS) to simultaneously analyze the composition of primary and secondary metabolites in mangosteen fruit pericarp, aril, and seed at four different ripening stages (stages 0, 2, 4, and 6). A total of 57 and 98 metabolites were identified from GC-MS and LC-MS analyses, respectively. These metabolites comprised various metabolite classes, including sugars and derivatives, amino acids and derivatives, organic acids, an alcohol, aldehydes, glycosides, fatty acids, phenolics, alkaloids, terpenoids, xanthones, and a quinone. Our results showed that metabolites with variable influence on projection (VIP) ≥ 1.00 and p ≤ 0.05 included primary metabolites (e.g., L-mannopyranose, myo-inositol, arabinofuranose, galacturonic acid, l-(+)-tartaric acid and aspartic acid) and secondary metabolites (e.g., neoisostegane, epirobinetinidol-(4β,8)-catechin, α-mangostin, and gartanin). Such metabolites may contribute to the degradation of the cell wall, development of flavor, color, and aroma, and defense against frugivores, insects, and pathogens during mangosteen ripening. The metabolic pathways of galactose, ascorbate, aldarate, starch, sucrose, cysteine, and methionine, as well as glycolysis and the tricarboxylic acid (TCA) cycle, were differentially regulated during mangosteen ripening. Profiling the fruit metabolome during the ripening provided a snapshot for understanding the intricate biological and molecular regulation of fruit development. Our results will facilitate further improvements in post-harvest technologies that will help increase the shelf life of mangosteen fruit, thus assisting farmers and producers in the global commercialization of this superfruit.

Water-soluble betaines and amines based on thiacalix[4]arene scaffold as new cholinesterase inhibitors.

Novel ammonium and betaine derivatives of p-tert-butylthiacalix[4]arene in cone and 1,3-alternate conformation were synthesized with high yields for the first time. The obtained compounds form in water spherical nanoparticles. It was shown by molecular docking calculations and in vitro experiments that amino and betaine derivatives can inhibit acetylcholinesterase and butyrylcholinesterase on the level of pyridostigmine while the toxicity of the obtained compounds is much lower than that of pyridostigmine.

Quantum chemical approach towards the secondary amino derivatives of C(3) substituted 1,4-naphthoquinone: Combined molecular and dft calculations

Abstract Here we present molecular geometry of 2-chloro-3-(N,N-dimethyl amino)-1,4-naphthoquinone; DCDA, 2-chloro-3-(N,N-diethyl amino)-1,4-naphthoquinone; DCDA-2, 2-chloro-3-(N,N-dipropyl amino)-1,4-naphthoquinone; DCDA-3; 2-bromo-3-(N,N-dimethyl amino)-1,4-naphthoquinone; DBDA, 2-bromo-3-(N,N-diethyl amino)-1,4-naphthoquinone; DBDA-2, and 2-bromo-3-(N,N-dipropyl amino)-1,4-naphthoquinone; DBDA-3 obtained by employing density functional theory using basic functional CAM-B3LYP. Single crystal X-ray structure was solved for DCDA-2 which crystallizes in P21/n space group. Molecular frameworks are significant with hydrogen bonding interactions and were observed via. O (2)∙∙∙H (13)∙∙∙C (13), two benzenoid moiety possess π-π stacking interactions. Effect on the electro-optic behavior by halogen and aliphatic chain has been addressed by similar level of theory. Furthermore it was presumed that asymmetric polarizability induced by these investigated compounds displays enhanced non linear response and could be considered potential candidates for electro-optic and nonlinear optical applications.