Dicarboxylic Acid Moieties Research Articles

Discrimination of subtypes of sesquiterpene pyridine alkaloids using a multistage ion fragmentation strategy

Sesquiterpene pyridine alkaloids (SPAs) are a large group of macrocyclic dilactones formed by dihydro-β-agarofuran sesquiterpenes and pyridine dicarboxylic acids, which have aroused widespread interest in the field of medicine due to their significant biological activities. In order to achieve accurate and rapid characterization of SPAs, previous studies have systematically investigated their fragmentation patterns in MS2, but there are still some problems that need to be resolved, such as distinction between wilfordate (W)- and evoninate (E)-subtypes, as well as determination of the substituent position. In this paper, a comparative analysis of W- and E-subtypes of SPAs was carried out by a product ion scanning-multistage fragmentation (PIS-MSn) strategy using ultra-high-performance liquid chromatography/linear ion trap quadrupole/orbitrap mass spectrometry (UHPLC/LTQ-Orbitrap-MS). The precursor ions for MSn were selected from the ions related with pyridine dicarboxylic acid moiety in MS2 spectrum, such as the ions at m/z 206, 178, and 160. The results showed that the product ions at m/z 104 or 117 were produced in the MS4 spectra of W-subtype SPAs ([M+H]+ > m/z 160 > m/z 132 > m/z 104 or 117). The ion at m/z 104 was produced when acetyloxyl group was present at C-5, whereas the ion at m/z 117 was produced when hydeoxyl group was present at C-5. Neither of the above characteristic ions were produced in the MS4 spectra of E-subtype SPAs. The fragmentation mechanism was also deduced. In addition, 13 SPAs were identified from the root of Tripterygium wilfordii, including 1 unknown compound using the MS/MS fragmentation pattern. The findings in this study enable the differentiation between W- and E-subtypes of SPAs and, to a certain extent, solve the problem of substituent position, which is of great significance for the accurate and in-depth identification of SPAs.

Recent Developments in the Design of New Water-Soluble Boron Dipyrromethenes and Their Applications: An Updated Review.

Boron-dipyrromethene (BODIPY) and its derivatives play an important role in the area of organic fluorophore chemistry. Recently, the water-soluble boron-dipyrromethene dyes have increasingly received interest. The structural modification of the BODIPY core by incorporating different neutral and ionic hydrophilic groups makes it water-soluble. The important hydrophilic groups, such as quaternary ammonium, sulfonate, oligoethylene glycol, dicarboxylic acid, and sugar moieties significantly increase the solubility of these dyes in water while preserving their photophysical properties. As a result, these fluorescent dyes are utilized in aqueous systems for applications such as chemosensors, cell imaging, anticancer, biolabeling, biomedicine, metal ion detection, and photodynamic treatment. This review covers the most current developments in the design and synthesis of water-soluble BODIPY derivatives and their wide applications since 2014.

Synthesis, Characterization and Antimicrobial Activity Evaluation of the Polybenzimidazole Derivatives with Different Dicarboxylic Acid Moieties

A series of polybenzimidazole was synthesized by the solution polycondensation reaction of 3,3´-diaminobenzidine (DAB) with dicarboxylic acid derivatives. The synthesized polybenzimidazoles were characterized by using IR, 1H-NMR, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). TGA and DSC studies showed that the polybenzimidazoles have good thermal stability and are generally amorphous in nature. Glass transition temperature (Tg) values were found to be in the range of 300-410°C. This is the first detailed study to investigate the antimicrobial activities of the polybenzimidazoles. The synthesized polybenzimidazoles have high antimicrobial activity compared to benzimidazole molecules. It was also found that they are more effective against bacterial species than fungal species. The polymers 2, 5, 6, 7, having -1,3-phenyl, vinyl, -1-OH-3,5-phenyl and 4,4´- oxybisphenyl rings, showed remarkable activity against tested bacterial species (MIC = 32-500 μg/mL). Among these polymers, the polymers 6 and 7 having additional electronegative moiety have the highest activity against tested bacterial species.

Synthesis and antiwear properties of dicarboxylic acid derivatives containing dialkyl dithiophosphate groups

AbstractThe use of lubricants has grown more widespread with industrial development. Lubricants usually contain additives with heavy metals such as zinc and molybdenum, increasing the emission of heavy metal contamination of soil and ocean. This study synthesised antiwear additives without heavy metal components in a simple and efficient manner by using alkane diacid derivatives produced from biomass and dithiophosphate instead of petroleum‐based compounds. A four‐ball wear test was performed to examine tribological performance in relation to changes in the alkyl chain length of the diacid and dithiophosphate of the synthesised antiwear additive, and the results were compared with the performance of zinc dialkyl‐dithiophosphorus (ZDDP), an antiwear additive that contains heavy metals. The tribological performance of the antiwear additives produced from synthesised dialkyl carboxylic acid derivatives was analysed based on the measurements of wear scar diameter. The wear scar diameter was 0.48 mm for the synthesised antiwear additive, whereas the ZDDP at a concentration of 0.05% gave a diameter of 0.82 mm. In the case of the synthesised antiwear additive, tribological performance did not improve for concentrations higher than 0.05%. An analysis of the carbon chain length of the dialkyl dithiophospate and dicarboxylic acid showed that the wear scar diameter was 0.72 mm when the alkyl chain length of R1 was 4. This diameter dropped below 0.48 mm when the alkyl chain length was greater than 8. When the number of carbons of dicarboxylic acid moiety was increased from 4 to 11, the antiwear performance improved slightly, with the wear scar diameter decreasing from 0.52 to 0.48 mm.

PO-423 Novel 4,5,6,7-tetrahydropyrazolo[1,5-a] pyridine fused chlorins as very active photosensitizers against melanoma and bladder cancer cells

Introduction Photodynamic therapy (PDT) is a clinically approved therapeutic procedure, which is entering the mainstream of cancer treatments. Nowadays PDT has been successfully used in the treatment of skin cancers, but the use of PDT against melanoma can be compromised due to the natural resistance mechanism of some melanoma cancer cells. Thus, the search for new photosensitizers is a relevant research goal. Bladder cancer is also an interesting target to PDT, due to easy irradiation accessibility by cystoscopy. Material and methods A375 human melanoma cells and HT1376 human bladder cancer cells were plated. The formulation of the sensitizers consisted in a 1 mg/mL solution in DMSO and the desired concentrations being achieved by successive dilutions. The sensitizers were administered in several concentrations (from 1 nM to 10 mM) and cells were incubated for 24 hour. Controls were performed on every test. Cells were washed with PBS and new drug-free medium was added. Each plate was irradiated with a fluence rate of 7.5 mW/cm2, to reach 10 J. Evaluation by MTT assay was performed 24 hour after the photodynamic treatment in order to evaluate the cytotoxic effect. Results and discussions Our previous in vitro PDT studies demonstrated that the increase of chlorins’ hydrophilicity of leads to higher activity against A375 melanoma cells. Therefore, a series of novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins bearing dicarboxylic acid and monocarboxyic moieties were developed showing an interesting biological activity against the A375 and HT1376 cancer cells. Inhibition of the metabolic activity seems to be dependent on the concentration of the sensitizers used. With the experimental metabolic activity values, it was possible to calculate the concentration of the sensitizers that inhibits the proliferation of cultures in 50% (IC50). For this series of compounds, IC50 values ranged from mM to nM concentrations. Nevertheless, a new molecule with an IC50 value of 67,93 nM stood out. Conclusion The compounds tested were active against human melanocytic melanoma A375 cells and human bladder HT1376 cancer cells. MTT assay showed that the metabolic activity was inversely proportional to the concentration of the photosensitizer. Interestingly low IC50 values in the nanomolar range encourage further studies. Funding The Foundation for Science and Technology: POCI-01–0145-FEDER-PTDC/QEQ-MED/0262/2014; (COMPETE 2020). POCI-01–0145-FEDER-007630 and POCI-01–0145-FEDER-007440.

Design, synthesis and tumor cell growth inhibitory activity of 3-nitro-2H-cheromene derivatives as histone deacetylaes inhibitors

As a continuous research for the discovery of coumarin-based targeted anticancer agents, we designed and synthesized a series of novel histone deacetylases (HDAC) inhibitors using the 8-ethoxy-3-nitro-2H-chromene as the surface binding or cap group, linear dicarboxylic acid or ω-amino acid moiety with different length as the linking motif, ortho-aminoanilides, amides or α-aminoamides as the zinc binding group and the internal cavity motifs. Most of these 3-nitro-2H-chromene derivatives exhibited good growth inhibitory activity against K562, A549, MCF-7, PC3 and Hela cells and were more potent than the reference drug SAHA and MS-275. At the concentration of 10µM, the ortho-aminoanilide series and the d-Phe derived α-aminoamide derivatives 16a and 16b displayed more potent activity toward HADC1 over HADC2, and only moderate to weak activity over HADC6. In contrast, the amide ZBG analogues, 12a and 12b, 14 and 15, were only moderate HDAC6 inhibitors, but more selective over HDAC1 and HDAC2. The ortho-aminoanilides 9b, 9c, 10b, 10c, 11b, and the α-aminoamides 16a and 16b were potent HADC1 inhibitors with the IC50 values in the nanomolar ranges. The ortho-aminoanilides 10b and10c with a phenyl internal cavity motif were more potent than MS-275 as HADC1 inhibitors and more selective over HADC2.

Discovery of Gemilukast (ONO-6950), a Dual CysLT1 and CysLT2 Antagonist As a Therapeutic Agent for Asthma.

An orally active dual CysLT1 and CysLT2 antagonist possessing a distinctive structure which consists of triple bond and dicarboxylic acid moieties is described. Gemilukast (ONO-6950) was generated via isomerization of the core indole and the incorporation of a triple bond into a lead compound. Gemilukast exhibited antagonist activities with IC50 values of 1.7 and 25 nM against human CysLT1 and human CysLT2, respectively, and potent efficacy at an oral dose of 0.1 mg/kg given 24 h before LTD4 challenge in a CysLT1-dependent guinea pig asthmatic model. In addition, gemilukast dose-dependently reduced LTC4-induced bronchoconstriction in both CysLT1- and CysLT2-dependent guinea pig asthmatic models, and it reduced antigen-induced constriction of isolated human bronchi. Gemilukast is currently being evaluated in phase II trials for the treatment of asthma.

Polymer Nanocomposites Containing N-Trimellitylimido-L-phenylalanine Dicarboxylic Acid Moieties Reinforced with α-Al2O3 Nanoparticles Modified with Citric Acid: Synthesis and Characterization

In field of nanotechnology, polymer based nanocomposites (NCs) with inorganic nanoparticles (NPs) have become a noticeable area of recent researches. In this work, citric acid (CA) was used as a biocompatible “modifier” for the alumina (α-Al2O3) NPs to prevent their agglomeration and create effective interaction with polymer matrix. In addition, chiral poly(amide-imide) (PAI) was synthesized by a direct polycondensation of N-trimellitylimido-L-phenylalanine dicarboxylic acid and 1,5-naphthalenediamine in ionic liquid as green solvent. Then modified (α-Al2O3-CA) NPs were incorporated into the obtained PAI through ultrasonic process for the preparation of PAI/α-Al2O3-CA NCs. Finally, the PAI/α-Al2O3-CA NCs were characterized by different methods.

Solvent-Responsive Self-Assembly of Amphiphilic Invertible Polymers Determined with SANS

Amphiphilic invertible polymers (AIPs) are a new class of macromolecules that self-assemble into micellar structures and rapidly change structure in response to changes in solvent polarity. Using small-angle neutron scattering (SANS) data, we obtained a quantitative description of the invertible micellar assemblies (IMAs). The detailed composition and size of the assemblies (including the effect of temperature) were measured in aqueous and toluene polymer solutions. The results show that the invertible macromolecules self-assemble into cylindrical core-shell micellar structures. The composition of the IMAs in aqueous and toluene solutions was used to reveal the inversion mechanism by changing the polarity of the medium. Our experiments demonstrate that AIP unimers self-assemble into IMAs in aqueous solution, predominantly through interactions between the hydrophobic moieties of macromolecules. The hydrophobic effect (or solvophobic interaction) is the major driving force for self-assembly. When the polarity of the environment is changed from polar to nonpolar, poly(ethylene glycol) (PEG) and aliphatic dicarboxylic acid fragments of AIP macromolecules tend to replace each other in the core and the shell of the IMAs. However, neither the interior nor the exterior of the IMAs consists of fragments of a single component of the macromolecule. In aqueous solution, with the temperature increasing from 15 to 35 °C, the IMAs' mixed core from aliphatic dicarboxylic acid and PEG moieties and PEG-based shell change the structure. As a result of the progressive dehydration of the macromolecules, the hydration level (water content) in the micellar core decreases at 25 °C, followed by dehydrated PEG fragments entering the interior of the IMAs when the temperature increases to 35 °C.

Sr2+ and Cd2+ coordination polymers: the effect of the different coordinating behaviour of a newly designed tricarboxylic acid

This article presents the investigation of the coordination behavior of a newly synthesized tricarboxylate ligand, obtained by joining imidazole dicarboxylic acid and 4-carboxybenzyl moieties [cbimdaH3, 1-(4-carboxybenzyl)-1H-imidazole-4,5-dicarboxylic acid]. Two novel coordination polymers were obtained through solvothermal reactions under similar conditions namely [Sr(cbimdaH)(H2O)]n (1) and [Cd2(cbimdaH)2(H2O)6]n·(DMF)3n(H2O)3n (2), with the ligand behaving as a dianionic tricarboxylate linker. The single crystal X-ray structures show that while 1 forms a 3D coordination polymer, 2 forms a 1D polymer which is further assembled in three dimensions through supramolecular interactions (H-bonding). Complex 1 consists of Sr2+ ions in a distorted dodecahedral coordination geometry, while 2 consists of Cd2+ ions in distorted pentagonal bipyramidal geometries. A topology study reveals that 1 has a new topology based on the 5,6-coordinated 3D net architecture. The luminescence properties of the complexes in the solid state and their thermal stabilities were studied.

A novel protein refolding system using lauroyl- l-glutamate as a solubilizing detergent and arginine as a folding assisting agent

More than 50 detergents, including acylated amino acid derivatives, were screened for their ability to solubilize and refold recombinant proteins expressed as inclusion bodies. Two model proteins, human interleukin-6 and microbial transglutaminase, were solubilized by these detergents and the solubilized proteins were rapidly diluted for testing their solubilization and refolding effectiveness. Long chain-acylated amino acid derivatives having dicarboxylic acid moieties were found to be superior to others under the conditions tested. In particular, lauroyl- l-glutamate (C12- l-Glu) showed the highest recovery of the native proteins. The effectiveness of dilution refolding was greatly improved by adding aggregation suppressive arginine into the refolding solvents. To gain understanding how this detergent works, interactions between detergents and proteins were examined using spectroscopic and native gel electrophoretic analyses, showing ideal properties for C12- l-Glu as a solubilzing agent, i.e. highly reversible nature of the detergent binding to the model globular proteins and of the conformational changes. These properties most likely have contributed to the effective protein solubilzation and refolding of inclusion bodies using C12- l-Glu and arginine.

Variation in acid moiety of polybenzimidazoles: Investigation of physico-chemical properties towards their applicability as proton exchange and gas separation membrane materials

A series of polybenzimidazoles (PBIs) were prepared from 3,3′-diaminobenzidine (DAB) and substituted aromatic dicarboxylic acids. Effects of added polarity, bulk and isomerism in the dicarboxylic acid moiety on the properties of formed aromatic polybenzimidazoles were investigated. Solution polycondensation procedure was optimized for individual case of PBI synthesis in order to obtain inherent viscosity of ≥1dL/g. Analysis of physical properties, water uptake, acid doping (H3PO4 and H2SO4) and gas permeability was performed. All these PBIs exhibited high thermal stability, good solvent solubility and amorphous nature. The uptake of H3PO4 varied from 9 to 20.1moles per repeat unit (mol/RU), H2SO4 uptake varied from 3.39 to 3.81mol/RU, while water uptake varied from 1.8 to 3.6mol/RU of PBI. The dibromoterephthalic acid and tert-butylisophthalic acid based PBI showed the highest H3PO4 uptake in the series, while tert-butylisophthalic acid based PBI exhibited the highest water uptake. Acid uptake was correlated with swelling of the PBI matrix, while density estimation of H3PO4-doped PBI by He gas expansion method could be correlated to the physical state of PBI. 5-tert-Butylisophthalic acid and 4,4′-(hexafluoroisopropylidene)bis(benzoic acid) based PBI exhibited higher H2 and O2 permeability than other PBIs. The ideal gas selectivity for O2/H2 was considerably higher for most of the PBIs than conventional gas separation membrane materials. These analyses suggested that some of these PBIs have a potential to be used as a PEM or gas separation membrane material.

Low‐energy collision‐induced fragmentation of negative ions derived from diesters of aliphatic dicarboxylic acids made with hydroxybenzoic acids

Diesters of ortho-hydroxybenzoic acid (salicylic acid) made with glutaric, adipic, and pimelic acids are the monomers of some potential drug candidates for aspirin patches. Collision-induced dissociation (CID) spectra of negative ion derived from these compounds show a 120-Da 'neutral loss' specific to the ortho isomers. In contrast, the anions derived from diesters of meta- and para-hydroxybenzoic acids show a 138-Da loss for an elimination of elements of hydroxybenzoic acid by a charge-remote mechanism. Deuterium labeling studies confirmed that the hydrogen atom transferred for hydroxybenzoic acid loss originates specifically from the alpha position of the dicarboxylic acid moiety. Although all spectra showed a peak at m/z 137, a charge-mediated process specific for the ortho compounds renders it the most prominent peak in the spectra of ortho compounds. Appropriate deuterium labeling experiments demonstrated that the hydrogen atom transferred for the formation of the m/z 137 ion in ortho compounds is specifically derived from the alpha position of the dicarboxylic acid moiety.

Arginine-modified DNA Aptamers That Show Enantioselective Recognition of the Dicarboxylic Acid Moiety of Glutamic Acid

We have screened glutamic acid-binding aptamers from a modified DNA pool containing arginine residues using the method of systematic evolution of ligands by exponential enrichment (SELEX). Thirty-one modified DNA molecules were obtained from the enriched pool after the 17th round of selection, and their binding affinities for the target were evaluated by binding assays using affinity gels. Three modified DNA molecules having higher affinity were sequenced and we determined their affinity and specificity for the target by surface plasmon resonance (SPR) measurements. The SPR studies indicated that two of these three aptamers distinguished the dicarboxylic acid moiety of the D-isomer from that of the L-isomer; however, the third aptamer did not show enantioselectivity.

Novel potent macrocyclic inhibitors of the hepatitis C virus NS3 protease: Use of cyclopentane and cyclopentene P2-motifs

Several highly potent novel HCV NS3 protease inhibitors have been developed from two inhibitor series containing either a P2 trisubstituted macrocyclic cyclopentane- or a P2 cyclopentene dicarboxylic acid moiety as surrogates for the widely used N-acyl-(4 R)-hydroxyproline in the P2 position. These inhibitors were optimized for anti HCV activities through examination of different ring sizes in the macrocyclic systems and further by exploring the effect of P4 substituent removal on potency. The target molecules were synthesized from readily available starting materials, furnishing the inhibitor compounds in good overall yields. It was found that the 14-membered ring system was the most potent in these two series and that the corresponding 13-, 15-, and 16-membered macrocyclic rings delivered less potent inhibitors. Moreover, the corresponding P1 acylsulfonamides had superior potencies over the corresponding P1 carboxylic acids. It is noteworthy that it has been possible to develop highly potent HCV protease inhibitors that altogether lack the P4 substituent. Thus the most potent inhibitor described in this work, inhibitor 20, displays a K i value of 0.41 nM and an EC 50 value of 9 nM in the subgenomic HCV replicon cell model on genotype 1b. To the best of our knowledge this is the first example described in the literature of a HCV protease inhibitor displaying high potency in the replicon assay and lacking the P4 substituent, a finding which should facilitate the development of orally active small molecule inhibitors against the HCV protease.

Potent inhibitors of the hepatitis C virus NS3 protease: Use of a novel P2 cyclopentane-derived template

The HCV NS3 protease is essential for replication of the hepatitis C virus (HCV) and therefore constitutes a promising new drug target for anti-HCV therapy. Several potent and promising HCV NS3 protease inhibitors, some of which display low nanomolar activities, were identified from a series of novel inhibitors incorporating a trisubstituted cyclopentane dicarboxylic acid moiety as a surrogate for the widely used N-acyl-(4 R)-hydroxyproline in the P2 position.

Degradation Behavior of Poly(ethylene glycol) Diblock and Multiblock Polymers with Hydrolytically Degradable Ester Linkages

Diblock and multiblock polymers of poly(ethylene glycol) containing degradable ester bonds between the blocks were synthesized and characterized. Monofunctional poly(ethylene glycol) (PEG 2000) was modified by aliphatic dicarboxylic acids (malonic, succinic, glutaric, maleic) to obtain monocarboxylic polymers PEG-COOH containing ester bonds. Diblock polymers (4000) were prepared by polycondensation of a diamine (ethane-1,2-diamine, L-lysine) and the semitelechelic PEG-COOH. The relationship between the structure of the linkage connecting two PEG blocks and the rate of its hydrolytic degradation was studied at pH 5.5, 7.4 and 8.0. The rate of hydrolysis of all polymers was significant already under mild alkaline conditions (pH 7.4 and 8.0) and increased with increasing pH. The ester bonds of polymers with saturated dicarboxylic acid moieties were stable at pH 5.5. However, the presence of double bond in the acid moiety substantially decreased the stability of the polymer not only in alkaline but also in acid medium. The results of this model study can be utilized in the design of biodegradable high-molecular-weight drug carriers and polymers for preparation of "stealth" systems intended for therapeutic application.

Solid-phase synthesis and bioevaluation of Lupeol-based libraries as antimalarial agents

The use of the triterpenoid lupeol as a scaffold for the synthesis of lupeol-based libraries is described. Lupeol was anchored to a solid support (Rink amide/Sieber Amide) through aliphatic dicarboxylic acid moieties, which also served as a site for introducing diversity. The resulting polymer linked 3β-O (resin-alkanoyl)-lup-20(29)-ene 3 was used to generate key intermediates 3β-O (resin-alkanoyl)-30-bromo-lup-20(29)-ene 4 and 3β-O (resin-alkanoyl)-30-amino-lup-20(29)-ene 6 for the generation of libraries based on disubstituted lupeol derivatives. A 96-member library was screened for its in-vitro antimalarial activity against Plasmodium falciparum.

Novel 12-deoxy-16-hydroxyphorbol diesters isolated from the seed oil of Jatropha curcas.

Six unstable intramolecular diterpene esters were isolated from the seed oil of Jatropha curcas. Five of these, Jatropha factors C(2)-C(6) (3-7), are new natural products, and the structure of the known Jatropha factor C(1) (2) has been revised. All compounds possess the same diterpene moiety, namely, 12-deoxy-16-hydroxyphorbol (1). The dicarboxylic acid moieties of 2-5 contain a bicyclo[3.1.0]hexane unit, and those of 6 and 7 a cyclobutane unit, which is described for the first time within this compound class. Compounds 4 and 5 are C-8' epimers. The structures of 2-7 were elucidated by spectroscopic methods and give an insight into the biogenesis of the characterized substances.

PH-responsive pseudo-peptides for cell membrane disruption

We describe pseudo-peptides obtained by the copolymerisation of l-lysine and l-lysine ethyl-ester with various hydrophobic dicarboxylic acid moieties. In aqueous solution, when the carboxylic acid groups are charged, the polymers dissolve. When they are fully neutralised the hydrophobic moieties cause the polymer to precipitate. The pH range over which reversible precipitation occurs can be adjusted by changing the intramolecular hydrophilic/hydrophobic balance, by using a carboxylic acid moiety with a different p K a value or by changing the apparent p K a value of the polymer through chemical modifications of the backbone. These bio-degradable materials are well tolerated by a range of mammalian cell lines at physiological pH but display an ability to associate with the outer membranes of these cells, which they rupture to varying degrees at pH 5.5. Relative to the degree of lysis displayed by poly( l-lysine iso-phthalamide), lysis was reduced by partial esterification and increased by replacing the aromatic iso-phthaloyl moiety with a long chain aliphatic dodecyl moiety. Similar behaviour was observed for the pH-dependent rupture of human erythrocytes, where poly( l-lysine dodecanamide) displayed enhanced cell lysis at pH values <7.0 relative to poly( l-lysine iso-phthalamide).