Free Carboxylic Acid Function Research Articles

Development of novel anilinoquinazoline-based carboxylic acids as non-classical carbonic anhydrase IX and XII inhibitors

As part of our ongoing endeavour to identify novel inhibitors of cancer-associated CA isoforms IX and XII as possible anticancer candidates, here we describe the design and synthesis of small library of 2-aryl-quinazolin-4-yl aminobenzoic acid derivatives (6a–c, 7a–c, and 8a–c) as new non-classical CA inhibitors. On account of its significance in the anticancer drug discovery and in the development of effective CAIs, the 4-anilinoquinazoline privileged scaffold was exploited in this study. Thereafter, the free carboxylic acid functionality was appended in the ortho (6a–c), meta (7a–c), or para-positon (8a–c) of the anilino motif to furnish the target inhibitors. All compounds were assessed for their inhibitory activities against the hCA I, II (cytosolic), IX, and XII (trans-membrane, tumour-associated) isoforms. Moreover, six quinazolines (6a–c, 7b, and 8a–b) were chosen by the NCI-USA for in vitro anti-proliferative activity evaluation against 59 human cancer cell lines representing nine tumour subpanels.

Ni‐Ferrite an efficient catalyst for synthesis of 3‐aryl substituted isoxazole‐5‐carboxylic acids via one‐pot multicomponent reaction

AbstractHere, we have reported an efficient one‐pot, three‐component reaction between various aryl aldehydes, NH2OH.HCl, and propargyl alcohol using Ni‐Fe2O4 as a nanocatalyst. Reactions were performed in ethanol at room temperature to obtain various 3‐aryl substituted isoxazole‐5‐carboxylic acids. The advantage of this protocol is that it formed isoxazole derivatives with free carboxylic acid functionality in one pot, which could transform into various other functional groups. This approach has several merits, including a quick reaction time, a wide range of substrates, excellent product yields, and reusable catalysts.

Waste Cooking (Palm) Oil as an Economical Source of Biodiesel Production for Alternative Green Fuel and Efficient Lubricant

Here, a cost-effective route for the preparation of biodiesel (BD) from waste cooking oil (WCO) as an alternative eco-friendly fuel and lubricant via catalytic transesterification process using simple base catalyst was demonstrated. Physical and chemical characterization based on FT-IR, 1H-NMR, and 13C-NMR spectroscopy reveals that free carboxylic acid functionality successfully alters to methyl ester of same hydrocarbon chain during the reaction. The BD was characterized by its physical, fuel characteristics including density, viscosity, acid value, flash point, pour point, and foaming tendency, and compared with existing diesel fuel in accordance with ASTM test standard. Prepared BD showed excellent fuel efficiency with higher flash (142 °C) and fire point (147 °C) than the existing diesel fuel. In order to use these synthetic biodiesel esters as advanced green lubricants, their lubrication behavior was tested and compared with hydrocarbon base oil hexadecane (HD). The macrotribological results showed the biodiesel significantly reduced the coefficient of friction by a maximum ~ 43% and specific wear rate ~ 71% in comparison with that of HD at variable applied load. The lubricating efficiency of prepared BD was found to be a similar trend in microtribometric experiments with reciprocating sliding motion under variable loads with similar contact pressure (Pm ~ 1.36–1.95 GPa) as demonstrated in macrotribological rotating motion. Due to polar nature of biodiesel, it deposits on the contact interface and provides a thick molecular film, which may be responsible for enhanced tribological behavior compared with pristine hydrocarbon oil.

Design and synthesis of immobilised orthopalladated catalyst for C[sbnd]C coupling

The new azo ligand 2-(2-(p-tolyldiazenyl)phenylamino)acetic acid, H2L, [formulated as H3CC6H4-N = N-C6H4-N(H)(CH2COOH)] was prepared. Reaction of H2L with Na2PdCl4 afforded the orthopalladated mononuclear [(HL)PdCl] complexes. The uncoordinated free dangling carboxylic acid function was recognized and confirmed by X-ray crystallographic studies. The [(HL)PdCl] complex was immobilized on Merrifield resin tethering with the free carboxylic acid function of the complex. Catalytic activity of orthpalladated [(HL)PdCl] complex in homogeneous media and Merrifield supported immobilized complex in heterogeneous phase, toward Suzuki cross-coupling reactions, were examined.

From dipivaloylketene to tetraoxaadamantanes

Dipivaloylketene (2) is obtained by flash vacuum pyrolysis of furan-2,3-dione 6 and dimerizes to 1,3-dioxin-4-one 3, which is a stable but reactive ketene. The transannular addition and rearrangement of enols formed by the addition of nucleophiles to the ketene function in 3 generates axially chiral 2,6,9-trioxabicyclo[3.3.1]nonadienes (bisdioxines) 4. When arylamines are used as the nucleophiles under neutral conditions, decarboxylation occurs during the formation of bisdioxines 8. However, when water or alcohols are added to 3 under acidic conditions, bisdioxine-carboxylic acids and esters 10 and 11 are obtained. Acid hydrolysis of the bisdioxines proceeds through the addition of water to a C=C double bond and results in a second transannular oxa-Michael-type reaction and generation of tetraoxaadamantanes 5. This reaction is decarboxylative when free carboxylic acid functions are present in the bisdioxines, thus forming 21 and 22, but carboxylic acid derivatives are preserved to yield compounds 20, 23, 25, 28, and 29. A hydrogenolysis of the dibenzyl ester 23 yields the free dicarboxylic acid 24. The tetraoxaadamantanes are formed in high yields (65–95%) in most cases, but the addition of water to the concave inside of the bisdioxines becomes severely hindered in cyclic derivatives, so that the 38-membered ring compound 32 requires microwave heating at 170 °C to form tetraoxaadamantane 33, and the catenated compound 36 and calix[6]arene derivative 37 did not form tetraoxaadamantanes. The reaction mechanisms of bisdioxine and tetraoxaadamantane formation are discussed.

Triterpenoid saponins from Clematis chinensis and their inhibitory activities on NO production

Four new triterpenoid saponins, clematochinenoside H–K (1–4), and five known structures (5–9), were isolated from the roots and rhizomes of Clematis chinensis. Their structures were elucidated on the basis of spectroscopic evidence and hydrolysis products. All isolates were evaluated for inhibitory effects against nitric oxide (NO) production in LPS-induced RAW 246.7 macrophages. Monodesmosidic saponins (1–3, 5, and 6) with a free carboxylic acid function at C-28 exhibited potent inhibitory activities with IC50 values in the range of 12.9–32.3μM, where as bisdesmosidic saponin (4, and 7–9) showed modest inhibitory effects with the inhibition ratios (%) from 39.9 to 59.0 at 50μM. In addition, the hydroxyl group at C-21 showed negative effect on the NO production inhibitory activity.

Elaboration of antibacterial plastic surfaces by a combination of antiadhesive and biocidal coatings of natural products

Antibacterial polyolefins surfaces, combining biocidal and antiadhesive properties, were elaborated by a covalent grafting of antimicrobial peptides (AMPs), able to kill adherent bacteria, on a pre-immobilized hyaluronic acid (HA) layer, able to repel the micro-organisms. Different HA activation rate for its immobilization, were used to change HA layer morphology and number of residual free carboxylic acid functions for AMPs grafting. Based on adhesion tests on Staphylococcus epidermidis and microscopy fluorescent observations, the presence of the two combined properties was shown to be depended on the HA activation rate. Thus, the best addition effect was observed for an AMP grafting on a surface based on a high HA activation, data pointing out a decrease of the bacterial adhesion up to 99.8% and a perturbation of the bacterial membrane integrity of adhered bacteria. On the contrary, a decrease of the antibacterial activity was observed for an AMP grafting on a surface based on a low HA activation.

Antiprotozoal Activity of Triazole Derivatives of Dehydroabietic Acid and Oleanolic Acid

Tropical parasitic diseases such as Chagas disease and leishmaniasis are considered a major public health problem affecting hundreds of millions of people worldwide. As the drugs currently used to treat these diseases have several disadvantages and side effects, there is an urgent need for new drugs with better selectivity and less toxicity. Structural modifications of naturally occurring and synthetic compounds using click chemistry have enabled access to derivatives with promising antiparasitic activity. The antiprotozoal activity of the terpenes dehydroabietic acid, dehydroabietinol, oleanolic acid, and 34 synthetic derivatives were evaluated against epimastigote forms of Trypanosoma cruzi and promastigotes of Leishmaniabraziliensis and Leishmania infantum. The cytotoxicity of the compounds was assessed on NCTC-Clone 929 cells. The activity of the compounds was moderate and the antiparasitic effect was associated with the linker length between the diterpene and the triazole in dehydroabietinol derivatives. For the oleanolic acid derivatives, a free carboxylic acid function led to better antiparasitic activity.

'Dual' peptidyl-oligonucleotide conjugates: Role of conformational flexibility in catalytic cleavage of RNA.

Traditional therapeutic interventions against abnormal gene expression in disease states at the level of expressed proteins are becoming increasingly difficult due to poor selectivity, off-target effects and associated toxicity. Upstream catalytic targeting of specific RNA sequences offers an alternative platform for drug discovery to achieve more potent and selective treatment through antisense interference with disease-relevant RNAs. We report a novel class of catalytic biomaterials, comprising amphipathic RNA-cleaving peptides placed between two RNA recognition motifs, here demonstrated to target the TΨC loop and 3'- acceptor stem of tRNAPhe. These unique peptidyl-oligonucleotide 'dual' conjugates (DCs) were created by phosphoramidate or thiol-maleimide conjugation chemistry of a TΨC-targeting oligonucleotide to the N-terminus of the amphipathic peptide sequence, followed by amide coupling of a 3'-acceptor stem-targeting oligonucleotide to the free C-terminal carboxylic acid functionality of the same peptide. Hybridization of the DCs bearing two spatially-separated recognition motifs with the target tRNAPhe placed the peptide adjacent to a single-stranded RNA region and promoted cleavage within the 'action radius' of the catalytic peptide. Up to 100% cleavage of the target tRNAPhe was achieved by the best candidate (i.e. DC6) within 4h, when conformational flexibility was introduced into the linker regions between the peptide and oligonucleotide components. This study provides the strong position for future development of highly selective RNA-targeting agents that can potentially be used for disease-selective treatment at the level of messenger, micro, and genomic viral RNA.

Multidrug-Containing, Salt-Based, Injectable Supramolecular Gels for Self-Delivery, Cell Imaging and Other Materials Applications.

Both molecular and crystal-engineering approaches were exploited to synthesize a new class of multidrug-containing supramolecular gelators. A well-known nonsteroidal anti-inflammatory drug, namely, indomethacin, was conjugated with six different l-amino acids to generate the corresponding peptides having free carboxylic acid functionality, which reacted further with an antiviral drug, namely, amantadine, a primary amine, in 1:1 ratio to yield six primary ammonium monocarboxylate salts. Half of the synthesized salts showed gelation ability that included hydrogelation, organogelation and ambidextrous gelation. The gels were characterized by table-top and dynamic rheology and different microscopic techniques. Further insights into the gelation mechanism were obtained by temperature-dependent 1 H NMR spectroscopy, FTIR spectroscopy, photoluminescence and dynamic light scattering. Single-crystal X-ray diffraction studies on two gelator salts revealed the presence of 2D hydrogen-bonded networks. One such ambidextrous gelator (capable of gelling both pure water and methyl salicylate, which are important solvents for biological applications) was promising in both mechanical (rheoreversible and injectable) and biological (self-delivery) applications for future multidrug-containing injectable delivery vehicles.

Concurrent Cellulose Hydrolysis and Esterification to Prepare a Surface-Modified Cellulose Nanocrystal Decorated with Carboxylic Acid Moieties

Cellulose nanocrystals (CNCs) were modified with natural di- and tricarboxylic acids using two concurrent acid-catalyzed reactions including hydrolysis of amorphous cellulose segments and Fischer esterification, resulting in the introduction of free carboxylic acid functionality onto CNC surfaces. CNC esterification was characterized by Fourier transform infrared spectroscopy, 13C solid state magic-angle spinning (MAS), and conductometric titration experiments. Average degree of substitution values for malonate, malate, and citrate CNCs are 0.16, 0.22, and 0.18, respectively. Despite differences in organic acid pKa, optimal HCl cocatalyst concentrations were similar for malonic, malic, and citric acids. After isolation of modified CNCs, residual cellulose coproducts were identified that are similar to microcrystalline cellulose based on SEM and XRD analysis. As proof of concept, recycling experiments were carried to increase the yield of citrate CNCs. The byproduct was then recycled by subsequent citric a...

Dimeric Labdane Diterpenes: Synthesis and Antiproliferative Effects

Several diterpenes with the labdane skeleton show biological activity, including antiproliferative effects. Most of the research work on bioactive labdanes has been carried out on naturally occurring diterpenes and semisynthetic derivatives, but much less is known on the effects of diterpene dimers. The aim of the present work was to synthesize dimeric diterpenes from the labdane imbricatolic acid using esters, ethers and the triazole ring as linkers. Some 18 new derivatives were prepared and the compounds were evaluated for antiproliferative activity on human normal fibroblasts (MRC-5) and the following human tumor cell lines: AGS, SK-MES-1, J82 and HL-60. The diethers 8–10, differing in the number of CH2 units in the linker, presented better antiproliferative activity with a maximum effect for the derivative 9. The best antiproliferative effect against HL-60 cells was found for compounds 3 and 17, with IC50 values of 22.3 and 23.2 µM, lower than that found for the reference compound etoposide (2.23 µM). The compounds 9, 17 and 11 were the most active derivatives towards AGS cells with IC50 values of 17.8, 23.4 and 26.1 µM. A free carboxylic acid function seems relevant for the effect as several of the compounds showed less antiproliferative effect after methylation.

Grafting of bifunctional phosphonic and carboxylic acids on Phynox: Impact of induction heating

Phynox, a cobalt–chromium alloy, exhibits interesting mechanical properties making it a valuable material for a number of applications. However, its applications (especially biomedical ones) often require specific surface properties that can be imparted via suitable surface functionalizations. Based on Faraday's law of induction, induction heating is a widely used method to heat metallic substrates directly and contactless. The aim of this work is to compare the influence of induction heating and a conventional heating method on the functionalization of Phynox surfaces with bifunctional (6-phosphonohexanoic and 11-phosphoundecanoic acids) monolayers in order to create a platform for a large variety of post-grafting chemical reactions, e.g. with alcohols and amines, to modify and control the surface properties. In a first part, we assess the influence of the heating method on the interaction between the two terminal moieties of the 6-phosphonohexanoic and 11-phosphoundecanoic acids and the Phynox surface by studying the grafting of n-dodecylphosphonic acid and n-dodecanoic acid separately. The suitability of such bifunctional molecules for post-grafting chemical reactions has then been assessed by studying the post-grafting of a fluorinated alcohol by the Steglich esterification reaction between the carboxylic end of the grafted bifunctional molecules and the alcohol function of the post-grafted molecule. It has been shown that induction heating can lead to a much more selective adsorption of bifunctional molecules on the surface of Phynox, leaving a higher amount of free carboxylic acid functions to react during the second modification step.

Detection of Macrophages Via Paramagnetic Vesicles Incorporating Oxidatively Tailored Cholesterol Ester: An Approach for Atherosclerosis Imaging

Macrophages play a key role in the initiation, progression and complications of atherosclerosis. In this article we describe the synthesis of biocompatible, paramagnetic, fluorescent phosphatidylserine vesicles containing cholesterol ester with a free carboxylic acid function and its use for targeted imaging of macrophages. We synthesized anionic vesicles containing a combination of phosphatidylserine and a novel synthetic oxidized cholesterol ester derivative (cholesterol-9-carboxynonanoate [9-CCN]). In vitro studies to characterize particle size, MRI relaxation times and stability were performed. Vesicles containing 9-CCN demonstrated enhanced ability to bind human low-density lipoprotein and to be internalized by macrophages. Experiments in cultured macrophages with 9-CCN vesicles, alone and in the presence of low-density lipoprotein, indicated uptake of vesicles through scavenger receptor and integrin-dependent pathways. In vivo MRI using 9-CCN vesicles containing gadolinium in a rabbit model of atherosclerosis revealed protracted enhancement of 9-CCN vesicles and colocalization with arterial macrophages not seen with control vesicles. Pharmacokinetic experiments demonstrated prolonged plasma residence time of 9-CCN vesicles, perhaps due to its capacity to bind to low-density lipoprotein. Vesicles containing 9-CCN demonstrate prolonged plasma and plaque retention in experimental atherosclerosis. Such a strategy may represent a simple yet clinically relevant approach for macrophage imaging.

Boronic Acid Catalysis for Mild and Selective [3+2] Dipolar Cycloadditions to Unsaturated Carboxylic Acids

Herein, the concept of boronic acid catalysis (BAC) for the activation of unsaturated carboxylic acids is applied in several classic dipolar [3+2] cycloadditions involving azides, nitrile oxides, and nitrones as partners. These cycloadditions can be used to produce pharmaceutically interesting, small heterocyclic products, such as triazoles, isoxazoles, and isoxazolidines. These cycloadducts are formed directly and include a free carboxylic acid functionality that can be employed for further transformations, thereby avoiding prior masking or functionalization. In all cases, BAC provides faster reactions, under milder conditions, with much improved product yields and regioselectivities. In some instances, such as triazole formation from the reaction of azides with 2-alkynoic acids, catalysis with ortho-nitrophenylboronic acid circumvents the undesirable product decarboxylation observed when using thermal activation. By using NMR spectroscopic studies, the boronic acid catalyst was shown to provide activation by a LUMO-lowering effect in the unsaturated carboxylic acid, likely via a monoacylated hemiboronic ester intermediate.

Synthesis and Characterization of New Biomedical Polymers: Serine- and Threonine-Containing Polyphosphazenes and Poly(l-lactic acid) Grafted Copolymers

Polyphosphazenes that contain serine and threonine side groups have been synthesized by the macromolecular substitution technique, and their structure and properties were determined. Serine and threonine have two different sites for covalent linkage to the polyphosphazene backbone. For one series of polymers, serine ethyl ester and threonine ethyl ester units were linked to the polyphosphazene skeleton via the N-terminus. The free hydroxyl groups on each side group were then used to graft poly(l-lactide). Graft densities of 1:0.5, 1:2, and 1:4 grafts per repeat unit were controlled through the stoichiometric ratios of sodium naphthalenide to polyphosphazene side groups during the synthetic procedures. For the second series of macromolecules, the hydroxyl function of serine or threonine was used as the site for covalent attachment to the polyphosphazene backbone, a process that required protection of both the N- and C-termini. Secondary reactions to remove the protective groups then yielded side units with free amino and carboxylic acid functions. These polymers (with serine or threonine groups linked via the hydroxyl function) are water-soluble over a broad pH range but have the ability to form ionic cross-links in the presence of calcium ions.

On-Line Synthesis of Pseudopeptide Library Incorporating a Benzodiazepinone Turn Mimic: Biological Evaluation on MC1 Receptors

Alpha melanocyte stimulating hormone (alpha-MSH) is a widely distributed hormone. This tridecapeptide exhibits various biological activities mediated through different receptors. alpha-MSH binds to the melanocortin-1 receptor (MC1-R), mainly expressed in keratinocytes and melanocytes, inducing melanogenesis and anti-inflammatory processes. The central His-Phe-Arg-Trp tetrapeptide sequence of alpha-MSH is known to form a turn in the bioactive conformation. To find new potent analogs of alpha-MSH, we decided to introduce non-peptide building blocks in the alpha-MSH sequence. Molecular modeling studies showed that two amino acids of the central core sequence could be replaced by the benzodiazepinone building block without loosing the beta-turn conformation. Benzodiazepines are well-known pharmacophores exhibiting a wide scope of biological activities and are described as constrained dipeptide mimics templates. Although numerous synthetic pathways leading to benzodiazepinones have been described in literature, no methodology has 1,4-benzodiazepine-2,5-diones building blocks bearing a free carboxylic acid function and a protected amino function suitable for incorporation into peptide sequences. In this study, we report the synthesis of peptides with a benzodiazepinone moiety obtained directly during the course of solid-phase peptide synthesis (SPPS). This "on-line" strategy leads to the generation of a 54-member pseudo-peptide library of alpha-MSH analogs. After LC/MS purification, binding assays were performed on the MC1 receptor leading to the discovery of several micromolar ligands.

Molybdenum carbonyl complexes with pyridylimino acidato ligands

Reactions of [Mo(CO)4(pip)2] with pyridine-2-carbaldehyde and the appropriate amino ester or amino acid produce complexes with chelated pyridylimino ligands bearing, respectively, an ester (1) or carboxylate (2a,b, 4, 5a,b) pendant arm, the structures of which have been determined by X-ray crystallography. In the case of alpha-amino acids, the resulting imino carboxylate complexes are unstable towards decarboxylation, this being complete for (R)-2-phenylglycine. The products of decarboxylation 3a-c were isolated and characterized, including X-ray structure determinations for and . In contrast, the derivatives of beta-alanine (4) and 3- and 4-aminobenzoic acids (5a,b) are stable towards decarboxylation. The structure determinations show that the pyridyliminocarboxylate complexes crystallize as salts with piperidinium cations, forming hydrogen-bonded ion-pair dimers featuring twelve- or eight-membered rings. Protonation of carboxylate complexes with 2 M HCl in CH2Cl2/water yields the corresponding neutral complexes 6a,b containing a free carboxylic acid functionality.

A short practical synthesis of 2′-deoxymugineic acid

A short and practical synthesis of 2′-deoxymugineic acid (DMA) has been developed via reductive alkylation with the aldehyde intermediates. No protection of azetidine-2-carboxylic acid was required and the presence of free carboxylic acid function facilitated purification by simple acid and base extractions. Furthermore, the intermediates were conveniently purified by HPLC due to the presence of chromophoric benzyl ester protecting group(s). Hydrogenolysis of the benzyl protecting groups in the final step furnished DMA in overall good yield.

The use of 3,3-bis(2-imidazolyl) propionic acid (bip-OH) as a new chelating ligand for Re(CO) 3 and Ru complexes: Formation of organometallic PNA oligomers with (bip)Re(CO) 3 and their interaction with complementary DNA

We report the use of 3,3-bis(2-imidazolyl) propionic acid (bip-OH, 1) as a new chelating bis(imidazole) ligand. The synthesis and full characterization of complexes Re(bip-O)(CO) 3 2 and [Ru(bpy) 2(bip-OH)] 2+ 3 is reported. Both complexes show interesting spectroscopic properties, namely IR for compound 2 and 1H NMR for 3, respectively. The free carboxylic acid functionality of 1 may be used for the coupling to biomolecules. We have prepared two peptide nucleic acid (PNA) decamers to which the rhenium complex 2 is coupled. All reactions were carried out by solid phase synthesis methods. The Re–PNA oligomer conjugates Re(CO) 3(bip– tgt cta gca a –NH 2) 4 and Re(CO) 3(bip– agg agc aac t-Lys–NH 2) 5 were obtained in good yield and high purity after HPLC purification and identified by their mass spectra. The interaction of 5 with complementary DNA yields a melting temperature of (53.9 ± 1) °C. This is the first DNA melting temperature reported for an organometallic metal–PNA conjugate.