Project description:The potential of bacterial cellulose as a carrier for the transport of ibuprofen (a typical example of non-steroidal anti-inflammatory drugs) through the skin was investigated. Ibuprofen and its amino acid ester salts-loaded BC membranes were prepared through a simple methodology and characterized in terms of structure and morphology. Two salts of amino acid isopropyl esters were used in the research, namely L-valine isopropyl ester ibuprofenate ([ValOiPr][IBU]) and L-leucine isopropyl ester ibuprofenate ([LeuOiPr][IBU]). [LeuOiPr][IBU] is a new compound; therefore, it has been fully characterized and its identity confirmed. For all membranes obtained the surface morphology, tensile mechanical properties, active compound dissolution assays, and permeation and skin accumulation studies of API (active pharmaceutical ingredient) were determined. The obtained membranes were very homogeneous. In vitro diffusion studies with Franz cells were conducted using pig epidermal membranes, and showed that the incorporation of ibuprofen in BC membranes provided lower permeation rates to those obtained with amino acids ester salts of ibuprofen. This release profile together with the ease of application and the simple preparation and assembly of the drug-loaded membranes indicates the enormous potentialities of using BC membranes for transdermal application of ibuprofen in the form of amino acid ester salts.
Project description:Pandanus tectorius (L.) Parkins. (PTPs) is rich in caffeoylquinic acids and amino acids, especially some essential amino acids, such as valine, phenylalanine, and so forth. A series of novel amino acid ester-coupled caffeoylquinic acid derivatives have been designed and synthesized. Biological evaluation suggested that some amino acid ester-coupled derivatives exhibited varying degrees of lipid-lowering effects on oleic acid-elicited lipid accumulation in HepG2 liver cells. Particularly, derivatives 6c, 6d, 6e and 6f exhibited comparable potential lipid-lowering effect with the positive control simvastatin and chlorogenic acid. Further studies on the mechanism of 6c, 6d, 6e and 6f revealed that the lipid-lowering effects were related to their regulation of TG levels and mRNA levels of lipometabolic-modulating genes, and merit further investigation.
Project description:Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)-2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor.
Project description:Nucleic acid vaccines have become a transformative technology to fight emerging infectious diseases and cancer. Delivery of such via the transdermal route could boost their efficacy given the complex immune cell reservoir present in the skin that is capable of engendering robust immune responses. We have generated a novel library of vectors derived from poly(β-amino ester)s (PBAEs) including oligopeptide-termini and a natural ligand, mannose, for targeted transfection of antigen presenting cells (APCs) such as Langerhans cells and macrophages in the dermal milieu. Our results reaffirmed terminal decoration of PBAEs with oligopeptide chains as a powerful tool to induce cell-specific transfection, identifying an outstanding candidate with a ten-fold increased transfection efficiency over commercial controls in vitro. The inclusion of mannose in the PBAE backbone rendered an additive effect and increased transfection levels, achieving superior gene expression in human monocyte-derived dendritic cells and other accessory antigen presenting cells. Moreover, top performing candidates were capable of mediating surface gene transfer when deposited as polyelectrolyte films onto transdermal devices such as microneedles, offering alternatives to conventional hypodermic administration. We predict that the use of highly efficient delivery vectors derived from PBAEs could advance clinical translation of nucleic acid vaccination over protein- and peptide-based strategies.
Project description:The crystal structures of two ammonium salts of 2-amino-4-nitro-benzoic acid are described, namely di-methyl-aza-nium 2-amino-4-nitro-benzoate, C2H8N+·C7H5N2O4-, (I), and di-butyl-aza-nium 2-amino-4-nitro-benzoate, C8H20N+·C7H5N2O4-, (II). The asymmetric unit of (I) comprises a single cation and a single anion. In the anion, small twists are noted for the carboxyl-ate and nitro groups from the ring to which they are connected, as indicated by the dihedral angles of 11.45 (13) and 3.71 (15)°, respectively; the dihedral angle between the substituents is 7.9 (2)°. The asymmetric unit of (II) comprises two independent pairs of cations and anions. In the cations, different conformations are noted in the side chains in that three chains have an all-trans [(+)-anti-periplanar] conformation, while one has a distinctive kink resulting in a (+)-synclinal conformation. The anions, again, exhibit twists with the dihedral angles between the carboxyl-ate and nitro groups and the ring being 12.73 (6) and 4.30 (10)°, respectively, for the first anion and 8.1 (4) and 12.6 (3)°, respectively, for the second. The difference between anions in (I) and (II) is that in the anions of (II), the terminal groups are conrotatory, forming dihedral angles of 17.02 (8) and 19.0 (5)°, respectively. In each independent anion of (I) and (II), an intra-molecular amino-N-H⋯O(carboxyl-ate) hydrogen bond is formed. In the crystal of (I), anions are linked into a jagged supra-molecular chain by charge-assisted amine-N-H⋯O(carboxyl-ate) hydrogen bonds and these are connected into layers via charge-assisted ammonium-N-H⋯O(carboxyl-ate) hydrogen bonds. The resulting layers stack along the a axis, being connected by nitro-N-O⋯π(arene) and methyl-C-H⋯O(nitro) inter-actions. In the crystal of (II), the anions are connected into four-ion aggregates by charge-assisted amino-N-H⋯O(carboxyl-ate) hydrogen bonding. The formation of ammonium-N-H⋯O(carboxyl-ate) hydrogen bonds, involving all ammonium-N-H and carboxyl-ate O atoms leads to a three-dimensional architecture; additional C-H⋯O(nitro) inter-actions contribute to the packing. The Hirshfeld surface analysis confirms the importance of the hydrogen bonding in both crystal structures. Indeed, O⋯H/H⋯O inter-actions contribute nearly 50% to the entire Hirshfeld surface in (I).
Project description:In a more synthetical approach to the study of ion-specific phenomena, four dipodal bis(guanidinium) siloxanes have been synthesized starting from glycine, β-alanine, γ-aminobutanoic acid, L-proline and 1,3-bis(3-aminopropyl)tetramethyldisiloxane. Together with their non-amide progenitor they were comparatively studied in regards to their interactions with nine different anions: sulphate, chromate, molybdate, benzoate, chloride, azide, nitrite, nitrate and thiocyanate. Their aqueous solubilities, form, 1H NMR and FT-IR spectra were examined while searching for anion-specific interactions falling in- or outside of the Hofmeister series. We show that although the "chao-" and "kosmotropic" ions affect the properties of solutions in a predictable way, more selective cation-anion pairing is responsible for phase separation and crystallinity. As a prominent example, crystal structure of one of the benzoate salts was successfully obtained and reveals a synergy of hydrophobic packing, ionic and hydrogen bonding. Immobilized but still flexible siloxane bridges give rise to crystals described by P 42/n space group and neatly segregated into hydro- and lipophilic sections.
Project description:This work represents the use of N-3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropanenitrile as a cyanoacetylating agent for the synthesis of cyanoacetamide benzoic acid and benzophenone derivatives by two different methods, namely, conventional heating and ultrasonication. The cyanoacetamide derivatives were subjected to cyclization to produce N-substituted 2-pyridone derivatives under conventional heating and by an ultrasonic method as well. The ultrasonic method afforded the products in less reaction time with high yields and purities compared to the conventional method, as observed from their spectral data. N-(4-Carboxy phenyl)-4,6-dimethyl-3-cyano-2-pyridone was coupled with different amino acid esters by the OxymaPure/DIC methodology under traditional and ultrasonic conditions. Again, ultrasonication assisted the coupling step and afforded the products with higher yields and purities compared to the traditional method. Fourier transform infrared spectroscopy, NMR (1H and 13C), elemental analysis, and LC-MS were used to determine the structures of all compounds. Finally, a feature of this protocol is exploring the utilization of ultrasonication as an eco-friendly alternative conventional heating method for N-cyanoacylation and synthesis of N-substituted pyridinone derivatives and as a coupling method for the formation of an amide bond, which might be of interest for many researchers.
Project description:The fluorophilicity of a series of hydrocarbon and fluorocarbon-functionalized nicotinic acid esters (nicotinates) is measured from their partitioning behavior (log K(P)) in the biphasic solvent system of perfluoro(methylcyclohexane) (PFMC) and toluene. The chain length of the hydrocarbon or fluorocarbon alkyl group of the ester ranges from one to twelve carbon atoms. Knowledge of the fluorophilicity of these solutes is relevant to the design of these prodrugs for fluorocarbon-based drug delivery. The experimental log K(p) values range from -1.72 to -3.40 for the hydrocarbon nicotinates and -1.64 to 0.13 for the fluorinated nicotinates, where only the prodrug with the longest fluorinated chain (2,2,3,3,4,4,5,5,6,6,7,7,8,8,8-pentadecafluorooctyl nicotinic acid ester) partitions preferentially into the fluorinated phase (log K(p) = 0.13). Predictions of the partition coefficients using solubility parameters calculated from group contribution techniques or molecular dynamics simulation are in reasonable agreement for the perhydrocarbon nicotinates and short chained perfluorinated nicotinates (≈ 0.3%-39% deviation). Significant deviations from experimental partition coefficients (greater than 100%) are observed for the longest chain perfluoroalkyl nicotinates.
Project description:An Ir-catalyzed enantioselective hydrogenation of 2-alkyl-pyridines has been developed using ligand MeO-BoQPhos. High levels of enantioselectivities up to 93:7 er were obtained. The resulting enantioenriched piperidines can be readily converted into biologically interesting molecules such as the fused tricyclic structures 5, 6, and 7 in 99:1 er, providing a novel, concise synthetic route to this family of chiral piperidine-containing compounds.
Project description:Chiral N-protected α-amino aryl-ketones are one of the useful precursors used in the synthesis of various biologically active compounds and can be constructed via Friedel-Crafts acylation of N-protected α-amino acids. One of the drawbacks of this reaction is the utilization of toxic, corrosive and moisture-sensitive acylating reagents. In peptide construction via amide bond formation, N-hydroxysuccinimide ester (OSu), which has high storage stability, can react rapidly with amino components and produces fewer side reactions, including racemization. This study reports the first synthesis and utilization of N-trifluoroacetyl (TFA)-protected α-amino acid-OSu as a potential acyl donor for Friedel-Crafts acylation into various arenes. The TFA-protected isoleucine derivative and its diastereomer TFA-protected allo-isoleucine derivative were investigated to check the retention of α-proton chirality in the Friedel-Crafts reaction. Further utilization of OSu in other branched-chain and unbranched-chain amino acids results in an adequate yield of TFA-protected α-amino aryl-ketone without loss of optical purity.