Том 67, № 4 (2018)

Modern medical diagnostics requires the detection of minor amounts of target proteins at the background of numerous different biological components. With rare exception, these problems cannot be solved by purely physical research methods. In this case, the simplest and efficient approach is concerned with the principles of complementary affine interactions of biopolymers. In this case, high sensitivity of the analysis is achieved by the introduction of labels with certain physical properties in affinity bioreagents. This review is focused on the development of proteomic studies and medical diagnostics with the use of colloidal quantum dots (QDs) as labels in affinity bioreagents. This review is devoted to the description of in vitro proteomic approaches used in the studies and diagnostics, where the problem related to toxicity is not as crucial as in therapy and no restrictions on the types and composition of QDs are imposed. In this case, QDs are considered to be one of the key components of a bioanalytical system. The problems of proteomic medical diagnostics are discussed from the viewpoint of analytical chemistry with the account for the structure and properties of macromolecular analytes and appropriate bioreagents.

An important goal of modern medicinal chemistry is to study the mechanisms of pain and analgesia in order to design effective analgesic drugs. Opioid analgesics are the gold standard for the treatment of severe pain; however, the use of opiates is associated with the development of side effects which are, in particular, related to the activation of the anti-opioid system. Mammalians synthesize a number of endogenous peptides, such as orphanin FGGFTGARKSARKLANQ, neuropeptide FF (FLFQPQRF-NH₂), tripeptide melanostatin (MIF) PLG-NH₂, as well as related compounds. These anti-opioid peptides are to one extent or another involved in homeostatic control of transmission of pain impulses. The present review includes the data published to date in domestic and foreign literature on the involvement of these peptides in such undesirable phenomena as inhibition of opioid analgesia, development of opioid tolerance and dependence, and hyperalgesia. Cell-cell and molecular ligand-receptor and receptor-receptor interactions of the opioid and anti-opioid systems are considered. These data can be useful for the design of new pharmaceuticals for pain relief. The generalization and study of these mechanisms are reflected in various approaches to treatment of pain syndromes and require analysis and further investigation.

A procedure was developed for the first time for simultaneous in vivo quantification of local aspartate and glutamate concentrations in the human brain using ¹H magnetic resonance spectroscopy (¹H MRS) and spectral J-editing. The MEGA-PRESS pulse sequence was modified to observe β-CH₂ nonequivalent proton resonances of aspartate (δ 2.65 and 2.80) and glutamate (δ 2.04 and 2.12) overlapped by signals of other metabolites. The frequencies, frequency selective pulse durations, and optimal echo times were selected by simulation and experimentally (for phantoms and in the brain in vivo).

A general scheme for the synthesis of oxazoline and benzoxazole derivatives of [17(20)E]-21-norpregnene differing in the structure of the steroid moiety as well as amides of 17β-hydroxy-3-oxopregn-4-en-21-oic and 17α-hydroxy-3-oxopregn-4-en-21-oic acids was developed. The scheme involved synthesis of the steroid building blocks (appropriately protected derivatives of pregn-17(20)-en-21-oic, 17β-hydroxypregnan-21-oic, and 17α-hydroxypregnan-21-oic acids) and subsequent transformation of these building blocks into the target compounds. Following the developed scheme, synthesis of new nitrogen-containing steroid derivatives exhibiting antiandrogenic activity was enabled.

Synthesis of analogs of tubuloclustin (N-(7-adamant-2-yloxy-7-oxoheptanoyl)-N-deacetylcolchicine (1)) with the colchicine fragment replaced with 2-methoxyestradiol scaffold attached via phenolic hydroxy group was described. Esters 3a–c exhibit moderate cytotoxicity (EC₅₀ = 5–6 μmol L^–1) and exert a weak effect on the microtubule network in A549 human lung carcinoma cells similar to the clustering effect of tubuloclustin and its derivatives. Conjugates 6a–c and 7a–c with the phenolic ester bond are low stable and compounds 7a–c are inactive to the microtubules of A549 cells, while compounds 6a–c cause an unusual effect of curling of the microtubules.

Due to the multifactorial nature of cancer diseases, investigations of combinations of the known cytostatics with substances that are chemosensitizers and act on various molecular target in the organism gain increasing significance. Polyfunctional compounds, whose molecules contain several reaction centers, serve as resources improving the efficiency of the chemosensitizing effect of various substances for chemotherapy by cytostatic agents. Classical representatives of such polyfunctional substances are sulfur-containing derivatives of alkylated phenols, the high oxidation activity of which is determined by a combination of the antiradical activity of the phenol fragments with the antiperoxide activity of the sulfur-containing groups. It is shown that the sulfur-containing phenolic antioxidant sodium S-[3-(3-tert-butyl-4-hydroxyphenyl) propyl] thiosulfate (TC-13) has no antitumor activity but enhances chemotherapeutic activity of cytostatic cyclophosphamide taken in a subtherapeutic dose, increasing the index of average life span of mice with leukemia P388 from 196 to 283%. In addition, a combination of TC-13 with the nitric oxide donor (NaNO₂) increases the antitumor activity of cytostatic cyclophosphamide by 110% for the same experimental model of mice at 50% survived animals.

New polyfunctional aromatic, nitroaromatic, and heterocyclic compounds linked to the 2,6-di-tert-butylphenol moiety via –NH–, –C(O)NH–, –S–, or–C=N– spacers were synthesized. These structures provide intramolecular charge transfer (ICT) and exhibit antioxidant activity. The structures of the new compounds were established by X-ray diffraction. The novel compounds were evaluated for antioxidant activity using the DPPH assay. The presence of the 2,4,6-trinitrophenyl moiety in combination with the –NH– spacer leads to a considerable increase in the antioxidant activity of 2,6-di-tert-butylphenols. These compounds are also weak lipoxygenase inhibitors. The results of this study provide an opportunity to search for new types of antioxidants with ICT.

In aqueous solutions at physiological temperature, the mechanism of antioxidative action of natural thiols (glutathione, cysteine, and homocysteine) mainly involves reactions with reactive oxygen species (ROS), peroxyl radicals and hydrogen peroxide. Reduction of hydrogen peroxide by thiols is accompanied by radical generation. The kinetic characteristics of these processes, including those for the reactions of hydrogen peroxide and glutathione immobilized on solid supports such as sodium montmorillonite (clay) and cellulose were determined. Prooxidative effects of thiols are related with the reactions of thiyl radicals formed in the exchange reactions of thiols with other radicals and in the reactions between thiols and hydroperoxides. Thiyl radicals are known to react easily with double bonds. Resveratrol and caffeic acid, phenolic antioxidants containing double bond in their molecules, were shown to be consumed when reacted with glutathione and the process accelerated in the presence of hydrogen peroxide.

Dihydropyrimidinethione podands, as well as podands containing 2-thienyl substituents have been synthesized via the multicomponent Biginelli reaction. Tuberculostatic activity of the novel podands was shown to depend on the polyether unit length. In particular, activity of dihydropyrimidinethione podands against laboratory strains of Mycobacterium tuberculosis, H₃₇Rv, M. avium, M. terrae, and the clinical strain of multi-drug resistant M. tuberculosis (MDR), increases with a shortening of the polyether unit length.

A water-soluble chitosan derivative, namely, N-succinylchitosan (NS-Chit), was used as a matrix for the formation of silver nanoparticles (AgNP) by metal ion re duction under influence of microwave irradiation in the presence of D-glucose as a reducing agent. The electron plasmon resonance spectra (λ_max = 410 nm) obtained for the irradiated solutions were typical of spherical silver nanoparticles. The in vitro tests confirmed a high bactericidal activity of the colloidal solution containing AgNP in a NS-Chit polymer matrix against strains of grampositive bacteria, namely, Bacillus subtillus (ATCC 6633), B. coagulans (429), and Staphylococcus aureus (ATCC 21027).

A complex of zinc with N-(5,6-dihydro-4H-1,3-thiazin-2-yl)benzamide (L) ligand, LZnCl₂, was synthesized for subsequent medical trials. The molar extinction coefficients were determined for LHBr solutions in water and physiological saline, and for LZnCl₂ ethanol solution. The ligand stability in various solvents was evaluated and the value of its protonation constant was found for the physiological saline solution, logK = 5.3±0.2. The impossibility of determination of the complex stability constant by the potentiometric titration method was demonstrated. The complex exhibited an insufficient stability in aqueous and physiological saline solutions, but was stable as the solution in alcohol. There was no sorption observed upon the treatment of ligand with hydroxyapatite nanoparticles, which could be a potential carrier for the therapeutic form of LZnCl₂, providing additional degrees of freedom for the interaction of ligand with cell membranes and a prolonged action of zinc ions.