Alexander M. Demin

Synthesis and Antiinflammatory and Analgesic Activity of Naproxen Amides with Amino Acid Derivatives

In recent years, there have been attempts to modify the well-known nonsteroidal antiinflammatory drugs by reactions with natural amino acids, aimed at eliminating undesired side effects of the drug action [1]. In particular, the synthesis of naproxen amide with glycine was reported in [2, 3]. The aim of this study was to obtain naproxen amides with some amino acid derivatives and characterize the products with respect to the antiinflammatory and analgesic activity and acute toxicity. The synthesis of naproxen amides (II – V) with methyl esters of (S )-methionine, (S )-phenylalanine, (S )-histidine, and (S )-leucine was based on the condensation of (S )-naproxen chloroanhydride (I) with the corresponding amino acid esters in DMF in the presence of triethanolamine (TEA) [4]:

Efficient large (ca. 40 g) laboratory scale preparation of (S)- and (R)-valine tert-butyl esters

A large laboratory scale (ca. 40 g) method for the preparation of enantiomerically pure (S)- and (R)-valine tert-butyl esters has been developed. The method involves three steps: preparation of N-TFA-valines, preparation of valine tert-butyl esters using 2-methylpropene in dioxane in the presence of sulfuric acid, and isolation of the target compounds as the acetate derivative. The overall yield is up to 70% relative to the starting valine, ee being more than 98% (by HPLC).

3-Aminopropylsilane-modified iron oxide nanoparticles for contrast-enhanced magnetic resonance imaging of liver lesions induced by Opisthorchis felineus

Purpose Liver fluke causes severe liver damage in an infected human. However, the infection often remains neglected due to the lack of pathognomonic signs. Nanoparticle-enhanced magnetic resonance imaging (MRI) offers a promising technique for detecting liver lesions induced by parasites. Materials and methods Surface modification of iron oxide nanoparticles produced by coprecipitation from a solution of Fe3+ and Fe2+ salts using 3-aminopropylsilane (APS) was carried out. The APS-modified nanoparticles were characterized by transmission electron microscopy, fourier transform infrared spectroscopy, and thermogravimetric analysis. Magnetic resonance properties of MNPs were investigated in vitro and in vivo. Results The amount of APS grafted on the surface of nanoparticles (0.60±0.06 mmol g−1) was calculated based on elemental analysis and infrared spectroscopy data. According to transmission electron microscopy data, there were no essential changes in the structure of nanoparticles during the modification. The APS-modified nanoparticles exhibit high magnetic properties; the calculated relaxivity r2 was 271 mmol−1 s−1. To obtain suspension with optimal hydrodynamic characteristics, amino groups on the surface of nanoparticles were converted into an ionic form with HCl. Cellular uptake of modified nanoparticles by rat hepatoma cells and human monocytes in vitro was 74.1±4.5 and 10.0±3.7 pg [Fe] per cell, respectively. Low cytotoxicity of the nanoparticles was confirmed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Annexin V/7-aminoactinomycin D flow cytometry assays. For the first time, magnetic nanoparticles were applied for contrast-enhanced MRI of liver lesions induced by Opisthorchis felineus. Conclusion The synthesized APS-modified iron oxide nanoparticles showed high efficiency as an MRI contrast agent for the evaluation of opisthorchiasis-related liver damage.

Surface modification of Fe3O4 magnetic nanoparticles with (S)-naproxen

Fe3O4 magnetic nanoparticles (MNPs) were obtained using the gas condensation method. These MNPs were modified with 3-aminopropylsilane (APS) through covalent bonding. The methods of qualitative and quantitative analysis of the modified MNPs were developed using UV and IR spectroscopy and inductively coupled plasma emission spectrometry (ICP-ES). It was established that the maximum loading level of APS on the surface of Fe3O4 MNPs was 0.91 mmol/g MNP. The study of the activity of the surface amino groups of the nanocomposites was carried out by the example of their modification with (S)-naproxen. The optimum conditions for coupling reaction were found. It was shown that the reaction proceeded most efficiently when using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as coupling agent in the presence of 1-hydroxy-1H-benzotriazole (HOBt). The maximum immobilization level of (S)-naproxen on the Fe3O4 MNP surface was 0.55 mmol/g MNP. Thus, the high reactivity of amino groups of the obtained nano-composites was shown, making it possible to further modify them.

Synthesis and Antiinflammatory and Analgesic Activity of Amino Acids Acylated with Ibuprofen

As is known, the ulcerogenic properties of nonsteroidal antiinflammatory drugs is a factor limiting their use in clinics. It was established that the side effects can sometimes be reduced by attaching a pharmacophore fragment to a natural amino acid residue. In this context, we have synthesized ibuprofen amides (I – III) by the condensation of ibuprofen chloroanhydride with methyl esters of amino acids (methionine, phenylalanine, histidine) using the method described elsewhere [1] and characterized the products with respect to the antiinflammatory and analgesic activity. The proposed structures of compounds I – III were confirmed by the results of elemental analyses and by H NMR data. According to the H NMR data, the synthesized amides represent diastereomers mixed in a 1 : 1 ratio.

pHLIP-modified magnetic nanoparticles for targeting acidic diseased tissue

Covalent immobilization of a pH-low insertion peptide (pHLIP) onto Fe3O4 magnetic nanoparticles was carried out resulting in the formation of MRI-visible materials able to specifically accumulate in acidic damaged tissue. The pH-dependent pHLIP-mediated binding of the obtained nanoconjugates to cells in acidic environment was demonstrated on HTC cells in vitro and in a mouse LLC tumour model in vivo.

Magnetic stromal layers for enhanced and unbiased recovery of co-cultured hematopoietic cells.

Cell co-culture systems have a long history of application in hematology and hold promise for successful hematopoietic stem and progenitor cell expansion. Here we report that various types of stromal cells used in such co-cultures can be rapidly and efficiently labeled with l-lysine-modified Fe3O4 magnetic nanoparticles. Hematopoiesis-supporting activity does not seem to be compromised after magnetic labeling of stromal cells, and the loss of the label by stromal layers during extended culturing is negligible. Magnetic labeling allows for simple and efficient removal of stromal component, yielding unbiased hematopoietic cell populations. When Lin(-) bone mouse marrow fraction was co-cultured with magnetic stromal layers and resulting cell populations were harvested by trypsinization, the yields of total nucleated cells, colony forming cells, and phenotypically primitive Lin(-)Sca-1(+)c-kit(+) subset were substantially higher as compared with nonadherent cell fractions harvested after conventional stromal co-culture. The advantage offered by the magnetic stroma approach over the traditional one was even more significant after a second round of co-culture and was more dramatic for more primitive hematopoietic cells. We conclude that magnetic stromal layers represent a simple, efficient, and convenient tool for co-culturing and subsequent recovery of sufficiently pure unbiased populations of hematopoietic cells.

Synthesis of enantiomers of N-(2-aminopurin-6-yl)amino acids

Nonracemic N-(2-aminopurin-6-yl)-substituted amino acids were synthesized by nucleophilic substitution of chlorine atom in 2-acetamido-6-chloropurine upon treatment with amino acid tert-butyl esters and subsequent removal of protecting groups. Their enantiomeric composition was determined by HPLC on chiral stationary phases.

PMIDA-Modified Fe3O4 Magnetic Nanoparticles: Synthesis and Application for Liver MRI

The surface modification of Fe3O4-based magnetic nanoparticles (MNPs) with N-(phosphonomethyl)iminodiacetic acid (PMIDA) was studied, and the possibility of their use as magnetic resonance imaging contrast agents was shown. The effect of the added PMIDA amount, the reaction temperature and time on the degree of immobilization of this reagent on MNPs, and the hydrodynamic characteristics of their aqueous colloidal solutions have been systematically investigated for the first time. It has been shown that the optimum condition for the modification of MNPs is the reaction at 40 °C with an equimolar amount of PMIDA for 3.5 h. The modified MNPs were characterized by X-ray diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy, thermogravimetric, and CHN elemental analyses. The dependence of the hydrodynamic characteristics of the MNP colloidal solutions on the concentration and pH of the medium was studied by the dynamic light scattering method. On the basis of the obtained data, we can assume that the PMIDA molecules are fixed on the surface of the MNPs as a monomolecular layer. The modified MNPs had good colloidal stability and high magnetic properties. The calculated relaxivities r2 and r1 were 341 and 102 mmol-1 s-1, respectively. The possibility of using colloidal solutions of PMIDA-modified MNPs as a T2 contrast agent for liver studies in vivo (at a dose of 0.6 mg kg-1) was demonstrated for the first time.

Correction: pHLIP-modified magnetic nanoparticles for targeting acidic diseased tissue

Correction for ‘pHLIP-modified magnetic nanoparticles for targeting acidic diseased tissue’ by A. M. Demin et al., RSC Adv., 2016, 6, 60196–60199.