The possibility of using carboxymethylcellulose as a platform for transporting ruthenium or bismuth ions in the body along with a medicinal preparation (a thiourea-derived NO synthase activator) was examined. Carboxymethylcellulose microgels were obtained by cross-linking with ruthenium or bismuth ions in a biological environment, and differences in their physicochemical parameters were identified. Furthermore, it was found that the size and aggregation stability of the microgels depend on the amount of the introduced organic ligand-drug.

In this work, double conjugate-microgels of Bi-CMC with different content of bismuth natural isotope were obtained and physicochemically characterized. The aggregative stability was demonstrated and the hydrodynamic and electrokinetic characteristics of Bi-CMC microgels under physiological conditions were quantitatively studied. The cytotoxicity of the obtained microgels was studied with respect to both tumor and healthy cells. The approach used to prepare microgels with stable bismuth ions was applied to obtain microgels cross-linked with radionuclide 207Bi with following parameters of decay: T1/2= 31.55 years, EC 99.962 %, beta+ 0.038 %. The obtained microgels labeled by 207Bi[Bi]3+ ions allowed a comparative analysis of the accumulation and organ distribution of radioactive ions within the microgel and free 207Bi3+ ions using a mouse model.

This analytical mini-review focuses on the effects of trace elements, which includes Cu, Mn, Zn, and Se, as well as some rarer microelements, on the regulation of oxidative stress in the body and of certain diseases associated with it. Synergism and competition between certain microelements have been considered a hot topic in the applied molecular pharmacology of these specific bio-effects. Some ideas for further possible directions of research are expressed. Noteworthy, metal coordinating catalytical sites of certain enzymes function as pharmacophore-forming and connecting nanostructures. These sites can be regarded as targets for various effectors, making them pharmacologically significant contributors to biocatalysis.

The influence of small amounts of ruthenium(iii) ions on the morphology, phase composition, and structure of the products formed under the conditions of hydroxyapatite (HAP) synthesis was studied by electron microscopy (including high resolution), energy dispersive analysis, and XRD. The introduction of doping ruthenium(iii) ions into the reaction medium at various stages of HAP formation affects the degree of aggregation of primary HAP—Ru nanoparticles. In the case of introducing Ru at the final stage of HAP synthesis, the formation of individual thread-like HAP—Ru nanoparticles is observed, but no formation of the intrinsic ruthenium phase is observed. The RuIII ions are distributed predominantly uniformly over the nanoparticle surface. The cocrystallization method for preparing composites of HAP with ruthenium radionuclides is promising for the development of new radiopharmaceuticals.

1,1-Dibenzyl-3-(1-benzyl-1 1H-pyrazol-4-yl)-2-methylisothioureas containing structural elements both of known antioxidants and glutamate receptor modulators were proposed as compounds with a dual mode of biological action, namely the antioxidant activity and the ability to influence the glutamatergic signaling system. The target compounds were synthesized by the reaction of substituted 4-amino-1-benzylpyrazoles with thiophosgene followed by the condensation of the resulting 1-benzyl-4-isothiocyanato-1H-pyrazoles with dibenzylamine and the subsequent S-methylation of the resulting thioureas. 1,1-Dibenzyl-3-[1-(3,4-dichlorobenzyl)- and 1,1-dibenzyl-3-[1-(2,4-dichlorobenzyl)-1H-pyrazol-4-yl]-2-methylisothioureas were found to have a moderate ability to protect neuroblastoma cells against the toxic effect of hydrogen peroxide, making these compounds interesting for further study of the modulatory activity toward glutamate receptors.

A new bismuth complex with the N-(5,6-dihydro-4H-1,3-thiazin-2-yl)benzamide ligand (L = C11H13N2OS) was synthesized for further medical use. The complex and the ligand exhibit anticancer activity. The structure of the complex was characterized by NMR spectroscopy, inductively coupled plasma atomic emission spectroscopy (ICP-AES), and laser-induced electron transfer desorption/ionization (LETDI) mass spectrometry. The Bi: L ratio is 1: 1; the components are connected by an ionic (ion-dipole) interaction. The reaction of bismuth(iii) chloride with ligand hydrobromide (L•HBr) affords the complex (C11H13N2OS)3[Bi2Cl9]. The composition of this complex was confirmed by X-ray diffraction, ICP-AES, and LETDI methods.

A new polyfunctional ligand of the thiadiazole family was synthesized. Cytotoxic properties with respect to leukemic cell lines, radiation stability, predicted permeability through the blood–brain barrier and cardiotoxicity of the new ligand and its precursor were determined. New zinc complexes with N-{2-[5-(3-chloro-4-methylphenylamino)-1,2,4-thiadiazol-3-yl]-1-methylethyl}-N-(2,2,6,6-tetramethylpiperidin-4-yl)-amine as the ligand have been obtained.

The use of hydroxyapatite obtained by enzymatic synthesis (HAPE) as a carrier of radionuclides (yttrium-90, copper(II) as a prototype of 64Cu and 67Cu and ruthenium-103 as a prototype of 97Ru) is considered. The processes of sorption and desorption of ions in different solutions are compared. The sorption of copper and yttrium on HAPE is almost irreversible, in contrast to the sorption of ruthenium, for which the reverse process depends on the medium.

Carboxymethylcellulose (CMC) complexes cross-linked with copper ions exhibit radiation stability, up to high doses of radiation (∼2000 Gy). A model estimate of the exit of copper ions from the CMC—Cu complexes, in which CMC can be a radionuclide ( 67 Cu 2+ ) carrier, showed that the dose load on the body does not increase for the calculated estimate of the real medical dose (∼750 Gy).

A comparative analysis of the pharmaceutical and radiopharmaceutical activity of zinc, copper, bismuth, and ruthenium ions was carried out. The prospects for their multimodal use on various platforms (carriers), including morphologically different hydroxyapatites obtained by various methods and carboxymethyl cellulose, are considered. A brief description of the possible applications of nanoparticles in medicine is given.

Using a mouse model, an organ distribution for microgels of carboxymethyl cellulose cross-linked with 67Cu2+ ions was investigated and compared with the distribution of free 67Cu2+ ions from 67CuCl2. The clearance of the microgels through both liver and kidneys was demonstrated. An additional examination of distribution for [3H]CMC microparticles and [3H]CMC–Cu microgels revealed no copper release from the microgels in vivo.

The search for new promising carries and vectors for the purposes of nuclear medicine with multifunctional effects is the most difficult problem in this branch of medicine. Among the components that are used to create carriers, one of the most perspective is the polysaccharide carboxymethylcellulose (CMC). This choice is due to CMC high solubility in aqueous and saline solutions, low toxicity, high biocompatibility, as well as the content of a large number of anionic (carboxyl) and hydroxyl functional groups, which are capable of strong binding of polyvalent metal ions. In our work CMC were bound to Cu2+ ions that resulted in a collapse of the polymer macromolecule and formation of the CMC-Cu2+ binary complexes. The binary complexes additionally adsorbed 2-aminopyrimidine (AP) and formed the CMC-Cu2+-AP ternary complexes. The binary and ternary complexes were characterized by dynamic light scattering, laser electrophoresis, UV-spectrophotometry, TEM- microscopy, thin layer chromatography and cell viability with the following main conclusions: (a) An increase in the copper content from up to 20 wt% leads to altering the size of CMC particles in water solution from 400 to 340 nm. Further binding of AP has no effect on the particle size. (b) In physiological solution, the size of the ternary complex particles was additionally decreased down to 200-220 nm. (c) The complex particles are stable against aggregation in water surrounding due to their total negative charge. (d) Their cytotoxicity in relation to leukemic cells significantly exceeds that in relation to normal lymphocytes, creating an attractive therapeutic window. The results show good prospects for the CMC-copper complexes as drug carriers.

Crystals of two copper complexes with N-(5,6-dihydro-4H- +1,3-thiazin-2-yl)benzamide were obtained and characterized by X-ray diffraction analysis. LETDI studies have shown that the composition of the complex is inhomogeneous, and the precipitated crystals can have different structures being of Cuii or Cui–Cuii types. The complexes are significantly more cytotoxic toward the leukemic Jurkat cell line than to healthy lymphocytes.

We synthesized eleven new amiridine-piperazine hybrids 5a-j and 7 as potential multifunctional agents for Alzheimer's disease (AD) treatment by reacting N-chloroacetylamiridine with piperazines. The compounds displayed mixed-type reversible inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Conjugates were moderate inhibitors of equine and human BChE with negligible fluctuation in anti-BChE activity, whereas anti-AChE activity was substantially dependent on N4-substitution of the piperazine ring. Compounds with para-substituted aromatic moieties (5g, 5h, and bis-amiridine 7) had the highest anti-AChE activity in the low micromolar range. Top-ranked compound 5h, N-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]quinolin-9-yl)-2-[4-(4-nitro-phenyl)-piperazin-1-yl]-acetamide, had an IC50 for AChE = 1.83 ± 0.03 μM (Ki = 1.50 ± 0.12 and αKi = 2.58 ± 0.23 μM). The conjugates possessed low activity against carboxylesterase, indicating a likely absence of unwanted drug-drug interactions in clinical use. In agreement with analysis of inhibition kinetics and molecular modeling studies, the lead compounds were found to bind effectively to the peripheral anionic site of AChE and displace propidium, indicating their potential to block AChE-induced β-amyloid aggregation. Similar propidium displacement activity was first shown for amiridine. Two compounds, 5c (R = cyclohexyl) and 5e (R = 2-MeO-Ph), exhibited appreciable antioxidant capability with Trolox equivalent antioxidant capacity values of 0.47 ± 0.03 and 0.39 ± 0.02, respectively. Molecular docking and molecular dynamics simulations provided insights into the structure-activity relationships for AChE and BChE inhibition, including the observation that inhibitory potencies and computed pKa values of hybrids were generally lower than those of the parent molecules. Predicted ADMET and physicochemical properties of conjugates indicated good CNS bioavailability and safety parameters comparable to those of amiridine and therefore acceptable for potential lead compounds at the early stages of anti-AD drug development.

Convenient synthesis path of nanostructured water-soluble microgels (PMG) based on carboxymethylcellulose cross-linked with zinc and ligand N-(5,6-dihydro-4H-1,3-thiazine-2 yl) benzamide and N-(4- isopropyl-phenyl)-N-(1-iminoethyl)piperidine-1-carbothioamide hydrobromides is described. Being insoluble in aqueous solutions the complex of zinc with the ligand acquires the solubility in water when dispersed in nanocontainers of PMG. Microgels were obtained by varying the content of zinc-ions in the reaction mixture. A new method for the determination of zinc in PMG composite using sulfarsazene is proposed. The resulting nanoparticles have been tested for cytotoxicity. It was established cytotoxicity of nanocontainers strongly depends on the concentration of zinc and ligand in composition of PMG.

A new method for separation of 97 Ru radionuclide from irradiated by a-particles molybdenum, which potentially could be applied in nuclear medicine, is proposed. Carrier-free ruthenium-97 was separated from macroamounts of molybdenum and trace amounts of technetium by extraction chromatography on a commercial DGA sorbent. The distribution of 97 Ru in the body organs of mice was studied.

Specific features of the interaction between bismuth(iii) and hydroxyapatite (HAP) of various morphologies during its sorption and co-crystallization binding were revealed. The obtained sorption isotherms nearly coincide with each other regardless of the HAP type used and cannot be described in terms of the Langmuir or Freundlich models. Bismuth can form the intrinsic phase of bismuth phosphate due to the chemical or topochemical reaction with HAP when the sorption method is used. In the case of co-crystallization binding of bismuth ions, the morphological modification of HAP occurs. The bismuth complexes with aminopyrimidine in neutral and weakly acidic solutions are readily hydrolyzed to form a precipitate, and no binding with HAP occurs.

Complexes of Biiii with 2-aminopyrimidine cations with metal-to-ligand ratios of 1:3 or 2:4 (depending on reaction conditions) were synthesized and characterized by elemental analysis, 1H NMR spectroscopy, and single crystal X-ray crystallography. The possibility of conversion of the latter complex into the former one was demonstrated. The determined cytotoxicity depended on the structure of these complexes.