Volume 51, Nº 10 (2018)
- Ano: 2018
- Artigos: 18
- URL: https://journals.rcsi.science/0091-150X/issue/view/15248
Molecular-Biological Problems of Drug Design and Mechanism of Drug Action
Prospects of a Search for Kappa-Opioid Receptor Agonists with Analgesic Activity (Review)
Resumo
Current approaches to the search for new kappa-opioid receptor (κ-OR) agonists with potential analgesic activity are reviewed. Agents with peripheral activity and biased agonists are most promising for development. Signal events initiated by κ-OR activation are considered. Chemical structures of presently known κ-OR agonists are presented.
Article
Captopril-Loaded Superparamagnetic Nanoparticles as a New Dual-Mode Contrast Agent for Simultaneous In Vitro/In Vivo MR Imaging and Drug Delivery System
Resumo
Superparamagnetic iron oxide nanoparticles (SPIONs) are widely applied as magnetic resonance imaging (MRI) contrast agents and drug carriers in drug delivery systems (DDSs) for diagnostics and treatment of diseases. Observation of drug delivery, drug release, and monitoring of the treatment can be performed by MRI. Magnetic nanoparticles (MNPs) can be used as dual-mode agents for simultaneous MRI contrast and drug delivery. Application of dual-mode MRI-contrast and drug-carrier agent is especially useful in targeted DDS. In this study, we report on the preparation of captopril-coated MNPs as a new dual-mode agent for simultaneous MRI contrast and DDS. The influence of contrast agent on the longitudinal (T1) and transverse (T2, T2*) relaxation times was studied and it was found that the effect on T2 and T2* exceeds the effect on T1, which leads to darkening of the MR image. Release of captopril from γ-Fe2O3@SiO2@captopril system was studied at three pH values and it was established that the drug release at pH 1.2 was greater than that at pH 4.8 and 7.4. The obtained results show that MNPs loaded with captopril can be used as dual-mode MRI contrast agent and DDS system.
Synthesis and Antiproliferative Activity Evaluation of Aryl(Hetaryl)Cyclopentenone Analogs of Combretastatin A-4
Resumo
A series of previously unreported di- and triaryl(hetaryl)cyclopentenone derivatives were prepared using a convenient synthetic method and screened preliminarily for antitumor activity in four human cell lines, i.e., T-cell leukemia (Jurkat), lung adenocarcinoma (A-549), colon cancer (HCT-116), and breast adenocarcinoma (MCF-7). The most cytotoxic of the tested compounds was 2-(3,4,5-trimethoxyphenyl)-3-(4-methoxyphenyl) cyclopent-2-en-1-one. However, it was inactive against lymphocytic leukemia P388 in mice despite its cytotoxicity in in vitro tests.
Synthesis and Biological Activity of β-Aroylacrylate Salts
Resumo
A series of β-p-toluylacrylate salts with various amines that retained the molecular fragment responsible for the antibacterial activity were synthesized. A new efficient method for obtaining β-aroylvinyl-1-pyridinium and -triphenylphosphonium bromides was proposed. Antibacterial testing showed that all investigated compounds possessed antibacterial properties.
Synthesis and Biological Activity of (Z)-Dialkylaminoalkylamides of N-Benzoyl-α,β-Dehydroamino Acids and Their Iodomethylates
Resumo
A series of N,N-(dialkylamino)alkylamides of several N-substituted α,β-dehydroamino acids and their quaternary ammonium salts were synthesized via the reaction of unsaturated 5(4H)-oxazolones with N,N-dialkyldiamines and characterized by physicochemical characteristics. Their reactions with human erythrocytic acetylcholinesterase (ACE) and plasmic butyrylcholinesterase (BuCE) were studied. The IC50 values [concentration at which the hydrolysis rate of cholinesterase was 50% inhibited by acetylthiocholine (0.1 mM)] of all synthesized compounds were determined. It was found that all synthesized compounds possessed anticholinesterase activity and were specific mainly for BuCE.
Antioxidant Properties of Fullerene C60/Dihydroquercetin Composites
Resumo
A complex of fullerene C60 and dihydroquercetin (DHQC) was synthesized. Its biological activity in a model system was studied using chemiluminometry. It was established that the C60/DHQC complex possessed antioxidant activity, which prompted further investigation of its biological effects. The structure of the complex will be elucidated in a continuation of this work using analytical HPLC and NMR spectroscopy.
QSAR Modelling of Thymidylate Synthase Inhibitors in a Series of Quinazoline Derivatives
Resumo
Thymidylate synthase (ThS) is a target for antimetabolite antitumor drugs. Such drugs have been used in the clinic although they cause several severe side effects and accumulate in tissues. Therefore, new less toxic ThS inhibitors must be sought and created. The GUSAR 2013 program was used to study the quantitative structure – activity relationship (QSAR) of a series of antifolate ThS inhibitors in the IC50 range 0.52 – 24,800.00 nM. Statistically significant QSAR models were constructed using MNA- and QNA-descriptors and self-consistent regression. They typically predicted highly accurately the structures of the training and test sets (\( {\mathrm{R}}_{\mathrm{train}}^2 \): 0.855 – 0.922; \( {\mathrm{R}}_{\mathrm{train}}^3 \): 0.810 – 0.895;\( {\mathrm{R}}_{\mathrm{test}1}^2 \): 0.734 – 0.790; \( {\mathrm{R}}_{\mathrm{test}2}^2 \): 0.800 – 0.835).
In Vitro Antitumor Activity of Newly Synthesized Pyridazin-3(2H)-One Derivatives via Apoptosis Induction
Resumo
Systemic toxicity associated with drug resistance continues to be the major obstacle to curative therapy of cancer. Tumor cell resistance to chemotherapeutic drugs often results in coordinate resistance to other structurally and functionally unrelated drugs and the subsequent development of cross resistance phenotype. Therefore, it seems necessary to identify new molecules as anticancer agents. In this process, we synthesized a series of new pyridazin-3(2H)-one derivatives and evaluated their antitumor potential. These cyclic molecules were synthesized and designed as a combination of benzofuran with pyridazinones. All final compounds have been characterized by spectral and elemental analyses to confirm successful synthesis reactions. To evaluate their anticancer activity, all derivatives were assessed against the human breast adenocarcinoma cell line (MCF-7) and the murine mastocytoma cell line (P815) using the methyl tetrazolium Test (MTT assay). The cytotoxic activity was found to be dose-dependent and the IC50 values of the synthesized compounds ranged from 14.5 to 40 μM against MCF-7 and from 35 to 82.5 μM against P815. At the same time, no cytotoxic activity was observed against normal cells. In order to investigate the molecular mechanism of the most cytotoxic product (6f), apoptosis induction was measured against MCF-7 cells. Using the annexin-V FITC staining technique, we showed that the cytotoxic effect of this product is associated with apoptosis induction.
β-Ionone-Derived Curcumin Analogs as Potent Anti-Inflammatory Agents
Resumo
A series of β -ionone-derived curcumin analogs (1a – 1j) have been synthesized by condensation of β -ionone with a variety of aldehydes. The synthesized compounds were screened for their in vitro anti-inflammatory activity against lipopolysaccharide (LPS)-induced expression of the pro-inflammatory cytokines tumor necrosis factor- α (TNF- α) and interleukin-6 (IL-6). Five active compounds exhibited dose-dependent inhibition of the release of TNF-α and IL-6. The active analogs represent a new class of anti-inflammatory agents with improved potency as compared to curcumin. Furthermore, the active compound 1e showed a protective effect against LPS-induced septic mortality in vivo. Our results suggest that the obtained analogs may be further developed as potential agents for the prevention and treatment of inflammatory diseases.
Design, Synthesis and Evaluation of Antitubercular Activity of Novel 1,2,4-Triazoles Against MDR Strain of Mycobacterium tuberculosis
Resumo
Emergence of various forms of resistant strains of Mycobacterium tuberculosis led to the exploration of drugs with novel mechanism of action. Recently econazole, an azole based antitubercular agent, attracted major attention for targeting mycobacterial cytochrome P450. In the present study, we designed novel 1,2,4-triazole derivatives based on econazole moiety and evaluated them for in vitro antitubercular activity against M. tuberculosis H37Rv and multi-drug resistant (MDR) strains of Mycobacterium.
Method Development for Quantitative Determination of Ascorbic Acid by High-Performance Thin-Layer Chromatography
Resumo
An economic and rapid procedure for identification and quantitative determination of ascorbic acid using high-performance thin-layer chromatography (HPTLC) was developed. The optimum conditions for chromatography of vitamin C on a thin layer of absorbent with quantitative interpretation of the HPTLC data were established experimentally and justified theoretically. The proposed procedure was validated using medicinal plant raw materials such as nettle leaves and sea-buckthorn fruit. The procedure could be used for quality control of substances, single-component and complex preparations, plant materials, biologically active supplements, premixes, and products of the food and cosmetics industries.
Search for New Drugs
Synthesis and Antiradical and Hemorheological Activity of Compounds Based on 2,6-Diisobornyl-4-Methylphenol and Polysaccharides
Resumo
Antiradical and hemorheological activities of conjugates synthesized from 2,6-diisobornyl-4-methylphenol (dibornol) and polysaccharides [inulin, carboxymethylcellulose, hydroxyethyl starch (HES)] were studied in vitro. The dibornol—HES polymer conjugate exhibited the greatest antiradical activity of the tested compounds for the water-soluble stable radical ABTS•+ and limited statistically significantly the blood viscosity increase in an in vitro blood hyperviscosity model at a final concentration of 10–5 g/ml of blood.
Author Correction
Medicinal Plants
Comparative Analysis of the Antimicrobial Activity of Extracts from Two Stonecrop Species (Sedum Maximum L. Hoffm. and S. Telephium L.)
Resumo
Extracts of S. maximum and S. telephium showed antimicrobial activity against Staphylococcus aureus ATCC 6538P, Pseudomonas aeruginosa ATCC 27835, and Escherichia coli ATCC 25922. The EtOH extract of S. maximum that was not purified by CHCl3 was most efficacious. The flavonoid contents in the extracts and their antimicrobial activities were correlated.
Drug Synthesis Methods and Manufacturing Technology
Preparation and Properties of Protamine/Pectin-Ag Biopolymer Microcapsules Containing a 2-Arylaminopyrimidine Derivative
Resumo
A synthetic 2-arylaminopyrimidine derivative (analog of imatinib mesylate) was incorporated into multilayer polyelectrolyte microcapsules prepared by alternating adsorption of protamine sulfate and pectin-Ag nanocomposite. The encapsulation effectiveness (EE) from an aqueous solution of the compound (4 mg/mL) was ~70% and reached 28 mass%. The release kinetics from the microcapsules depended significantly on the solution pH and ionic strength. Release of the imatinib analog was prolonged most in alkaline solutions. In vitro experiments on hemoblast suspension cultures showed that microencapsulation of the 2-arylaminopyrimidine derivative changed its antitumor activity and lowered the IC50 value by 1.4 – 2.2 times.
Structure of Chemical Compounds, Methods of Analysis and Process Control
Certification of Reference Standards in Pharmacy: Mass Balance Method
Resumo
Approaches to certification of substances as reference standards (RSs) by the mass-balance method and the restrictions that must be considered when using this method are considered. Formulas for estimating the uncertainty of certified values are presented. Also, formulas missing from the literature are given to assess a) the uncertainty in the contents of organic impurities obtained by normalization of peak areas (heights) with correction factors and b) the uncertainty in the detection limits of the organic impurities. Recommendations for correct certification of reference standards by the mass-balance method are provided.