INFLUENCE OF COPPER COMPLEXES [Cu(PTA)4]BF4 AND [Сu(acac)2] ON RATS IRRADIATED WITH RADIOISOTOPE TECHNETIUM

One of the priority tasks of modern radiobiology is the search for new, effective radioprotective compounds. In this area, metal complexes with high antioxidant activity are of particular interest. In order to study the possible favorable radioprotective effect of two copper complexes in different oxidation states, [Cu(PTA)4]BF4 and [Сu(acac)2], on the irradiated organism, we studied cytogenetic parameters in 4 groups of experimental animals. Group I included intact animals; Group II consisted of animals exposed to technetium (Tc) radioisotope, which were intraperitoneally injected with an isotope with an activity of 4.8 mCi in a volume of 2 mL - "pure irradiation"; Group III consisted of animals that were intraperitoneally injected with the copper(I) complex [Cu(PTA)4]BF4 at a dose of 50 mg/kg in a volume of 2 mL one hour before the administration of the Tc isotope (“irradiation + [Cu(PTA)4]BF4”). Group IV included animals that received the copper(II) complex [Сu(acac)2] before irradiation. We studied survival and cytogenetic parameters, determined the mitotic index, chromosomal aberrations and the percentage of polyploid cells. The survival rate of group II was 40%. In the group of intact animals, as well as in groups III and IV the survival rate was 100%. The dynamics of survival was described by regression equations, which make it possible, by means of extrapolation, to determine the change in the percentage of survival in the long term of the experiment and to predict the further outcome of the experiment. Investigating cytogenetic indicators, for all 3 indicators, a significant difference was found between intact and irradiated animals, i.e. these indicators can be considered as markers of technetium isotope exposure. In terms of proliferative activity, a significant difference was found in irradiated animals compared with groups III and IV, which indicates the radioprotective property of both the copper compounds. As for the [Cu(acac)2], when it was used in group IV and compared with others, we obtained a pronounced significant difference from the group with “pure irradiation” in all studied cytogenetic parameters. It was found that the copper complexes [Cu(PTA)4]BF4 and [Cu(acac)2] have the ability to prevent or mitigate the effect of ionizing radiation on an animal's body. Based on cytogenetic parameters, it can be concluded that these compounds promote reparative processes in the bone marrow cells of irradiated animals. Multiregression analysis of cytogenetic parameters confirmed the highest efficiency of the copper(II) complex [Cu(acac)2]. The results of the research indicate the need to continue work in the direction of searching for agents that have a therapeutic effect in radiation injuries

Therapeutic potential of the phosphino Cu(I) complex (HydroCuP) in the treatment of solid tumors

[Cu(thp)4][PF6] (HydroCuP) is a phosphino copper(I) complex highly soluble and stable in physiological media that has been developed as a possible viable alternative to platinum-based drugs for anticancer therapy. HydroCuP potently inhibited the growth of human cancer cells derived from solid tumors by inducing endoplasmatic reticulum (ER) stress thus leading to cell death through paraptosis with a preferential efficacy against cancer rather than non-cancer cells. Aim of the present study was to assess the therapeutic potential of HydroCuP in vivo, in syngenic and xenograft murine models of solid tumors by triggering the Unfolded Protein Response (UPR) pathway. With respect to platinum drugs, HydroCuP induced a markedly higher reduction of tumor growth associated with minimal animal toxicity. In human colorectal cancer xenografts, chemotherapy with HydroCuP was extremely effective in both oxaliplatin-sensitive and resistant models. The favorable in vivo tolerability of HydroCuP was also correlated to an encouraging biodistribution profile. Additionally, no signs of drug-related neurotoxicity and nephrotoxicity were observed. Altogether, these results demonstrate that HydroCuP appears worth of further investigation to evaluate its therapeutic activity towards a broad spectrum of solid malignancies

Changes in blood indicators in case of use of bis[bis(3,5-dimethylpyrazol-1-yl)acetato]copper(II) complex after burn injuries

Burn injuries cause profound changes in hematological parameters. The degree of severity of such changes and the speed of development of disturbances depend on the quantitative parameters of the injuries (area and degree of damage). One of the most urgent modern healthcare problems is the search and development of new effective approaches and medications for healing burn injuries. Radioprotectors differ by their effectiveness and duration of their protective action. For the purpose of promotion of tissue regeneration after burn injuries, medications with anti-inflammatory, analgesic and pro-regenerative properties are used. In this regard, copper-based complexes are of particular interest. The biogenic role of copper includes its participation in the processes of hematopoiesis. Copper also plays an important role in neutralizing the toxins of microorganisms, in prolongation of the action of antibacterial medications, as well as in reducing inflammatory reactions. The use of copper sulfate promotes the acceleration of skin regeneration in burn wounds, and Cu complexes show low toxicity. The aim of the study is to identify a possible positive effect of the bis[bis(3,5-dimethylpyrazol-1-yl)acetato]copper(II) complex, Cu[HC(COO)(pzMe2)2]2, in case of burns. As a result of hematological and cytogenetic studies, it was found that Cu[HC(COO)(pzMe2)2]2 has the ability to prevent or reduce the pathological processes in case of deep burns. The findings were also confirmed by survival assessments (100%)

INFLUENCE OF A COPPER(II) COMPLEX SUPPORTED BY ACETYLACETONATES ON SURVIVAL, CYTOGENETIC PARAMETERS AND BLOOD PARAMETERS OF ANIMALS WITH III-AB DEGREE BURNS

One of the priority tasks of modern medicine is the search for new effective means that contribute to the treatment of burn injuries. In this area, metal complexes based on copper are of particular interest. The aim of the work is to evaluate the possible beneficial effect of a Cu(II) complex supported by acetylacetonates, [Cu(acac)2], on thermal burns by determining toxicity, analyzing survival and some cytogenetic and blood parameters. The metal complex [Cu(acac)2] turned out to be a low-toxic compound: the LD50/7 value was 1815 mg/kg. The study of survival, blood counts and cytogenetic parameters showed a beneficial effect of the [Cu(acac)2]. Studies have shown that in the early stages after the burn in animals injected with [Cu(acac)2], there is a significant decrease in blood clotting time (BCT) and hematocrit, an increase in the number of leukocytes. There is also a significant decrease in the levels of platelets, erythrocytes and hemoglobin. By the end of the experiment, there was a trend towards normalization of hematological parameters. The dynamics of the survival of animals from the group "burn + injections of the metal complex" with the corresponding regression curve and an equation that allows using extrapolation to predict the change in the percentage of survival in the long term of the experiment is given. The processes of wound healing, epithelialization, hair growth in the “burn + [Cu(acac)2]” group are more intense than in the pure burn group, which indicates the beneficial effect of this metal complex on the burned organism

Changes in cytogenetic indicators promoted by the copper(II) complex Cu[HC(COO)(pzMe2)2]2 before irradiation

One of the most urgent problems of modern radiobiology is the search and development of new effective radioprotectors. Radiation damage causes physiological disturbances and profound changes in hematological indicators. The severity of such changes and the speed of development of disturbances are dose-dependent. Radioprotectors differ by their effectiveness and duration of their protective action. They should be non-toxic, effective, not cause pronounced adverse reactions, act relatively quickly and for a long time. In this regard, copper coordination compounds are of particular interest. The main biogenic role of copper is to participate in the processes of hematopoiesis. It is involved in the neutralization of the toxins of microorganisms, as well as prolongs the action of antibacterial medications, and reduces inflammatory reactions. Copper complexes have low toxicity and pronounced radioprotective properties. The aim of the study is to identify the possible radioprotective effects of the bis[bis(3,5-dimethylpyrazol-1-yl)acetato]copper(II) complex, based on cytogenetic analysis. As a result of cytogenetic studies, it was found that Cu[HC(COO)(pzMe2)2]2 has the ability to prevent or weaken the effect of ionizing radiation. The findings were also confirmed by survival assessments (80%). It can be concluded that this compound promotes reparative processes in the bone marrow cells of irradiated animals

COMPARATIVE ANALYSIS OF TOXICITY OF BIS[BIS(3,5-DIMETHYLPYRAZOL-1-YL)ACETATO]COPPER AND CU 2 (3,5- DIPS) 4 (H 2 O) 3 COPPER(II)-BASED COMPLEXES

One of the priority tasks of modern medicine is the search for new effective means of facilitating the treatment of injuries of various nature. Besides the stability, ease of use and prolonged action, the requirements for such compounds also include low toxicity. In this regard, copper-based complexes with high antioxidant activity are of particular interest. The aim of this work is to determine and compare the toxicity of bis[bis(3,5-dimethylpyrazol-1-yl)acetato]copper(II) complex, (Cu[HC(COO)(pzMe2)2]2 (complex 1) and Cu2(3,5-DIPS)4(H2O)3 (complex 2) by evaluating the survival, life expectancy and several blood parameters. According to the obtained data, complexes 1 and 2 proved to be low-toxic compounds. According to the test results: in case of complex 1 at a dose of 1450 mg/kg, we received a survival rate of 87,5%, and an average life expectancy of 26,8 days, and in the case of complex 2 at the same dose, the survival rate was 75% and the average life expectancy was 22,9 days, which indicates the low toxicity of these compounds (complex 2 has however a higher toxicity, since an identical result is achieved with a lower dose). Using the method of integration according to Behrens in experiments on rats, an average lethal dose of LD50/7 was found, which is more than 2000 mg/kg. Regarding the blood parameters: in case of complex 1, on the 3rd day of the experiment, an increase in the level of all studied blood parameters was observed. This was followed by a decrease, and on the 7th day there was a normalization of all blood parameters except for the number of platelets. Nevertheless, a trend towards normalization was observed in this indicator as well, which led to the normal value of platelet levels by the 21st day. When complex 2 was administered subcutaneously, a significant decrease in hemoglobin level was observed, which was restored by the 7th day; a significant decrease in blood clotting time (BCT), which persisted until the end of the study. By the 7th day, a significant decrease in the levels of platelets and erythrocytes was also noted. The results of haematological studies also confirmed the lowest toxicity of complex 1

An Efficient Lewis Acid Catalyzed Povarov Reaction for the One-Pot Stereocontrolled Synthesis of Polyfunctionalized Tetrahydroquinolines

An easy and efficient synthetic methodology for the one-pot stereocontrolled synthesis of tetrahydroquinolines through Lewis acid activated Povarov reaction is described. The protocol takes advantage of the very cheap, easy to handle, and environmentally friendly cerium trichloride as catalyst and allows to obtain either the anti- or the syn-isomer of the final tetrahydroquinoline with good selectivity, by performing the reaction in solvent or solventless conditions. The scope of the reaction is expanded to the one-pot synthesis of N-alkyltetrahydroquinolines through a very efficient iminium-Povarov approach. A deeper insight on the reaction system was provided by the study on the side reactions occurring in the reaction conditions and on the nature of the stereoselectivity

Synthesis and cytotoxicity studies of Cu(I) and Ag(I) complexes based on sterically hindered β-diketonates with different degrees of fluorination

Design, synthesis, and in vitro antitumor properties of Cu(i) and Ag(i) phosphane complexes supported by the anions of sterically hindered & beta;-diketone ligands, 1,3-dimesitylpropane-1,3-dione (HLMes) and 1,3-bis(3,5-bis(trifluoromethyl)phenyl)-3-hydroxyprop-2-en-1-one (HLCF3) featuring trifluoromethyl or methyl groups on the phenyl moieties have been reported. In order to compare the biological effects of substituents on the phenyl moieties, the analogous copper(i) and silver(i) complexes of the anion of the parent 1,3-diphenylpropane-1,3-dione (HLPh) ligand were also synthesized and included in the study. In the syntheses of the Cu(i) and Ag(i) complexes, the phosphane coligands triphenylphosphine (PPh3) and 1,3,5-triaza-7-phosphaadamantane (PTA) were used to stabilize silver and copper in the +1 oxidation state, preventing the metal ion reduction to Ag(0) or oxidation to Cu(ii), respectively. X-ray crystal structures of HLCF3 and the metal adducts [Cu(L-CF3)(PPh3)(2)] and [Ag(L-Ph)(PPh3)(2)] are also presented. The antitumor properties of both classes of metal complexes were evaluated against a series of human tumor cell lines derived from different solid tumors, by means of both 2D and 3D cell viability studies. They display noteworthy antitumor properties and are more potent than cisplatin in inhibiting cancer cell growth

Exploring the Antitumor Potential of Copper Complexes Based on Ester Derivatives of Bis(pyrazol-1-yl)acetate Ligands

Bis(pyrazol-1-yl)acetic acid (HC(pz)(2)COOH) and bis(3,5-dimethyl-pyrazol-1-yl)acetic acid (HC(pz(Me2))(2)COOH) were converted into the methyl ester derivatives 1 (L-OMe) and 2 (L-2OMe), respectively, and were used for the preparation of Cu(I) and Cu(II) complexes 3-10. The copper(II) complexes were prepared by the reaction of CuCl2 center dot 2H(2)O or CuBr2 with ligands 1 and 2 in methanol solution. The copper(I) complexes were prepared by the reaction of Cu[(CH3CN)(4)]PF6 and 1,3,5-triaza-7-phosphaadamantane (PTA) or triphenylphosphine with L-OMe and L-2OMe in acetonitrile solution. Synchrotron radiation-based complementary techniques (XPS, NEXAFS, and XAS) were used to investigate the electronic and molecular structures of the complexes and the local structure around copper ions in selected Cu(I) and Cu(II) coordination compounds. All Cu(I) and Cu(II) complexes showed a significant in vitro antitumor activity, proving to be more effective than the reference drug cisplatin in a panel of human cancer cell lines, and were able to overcome cisplatin resistance. Noticeably, Cu complexes appeared much more effective than cisplatin in 3D spheroid cultures. Mechanistic studies revealed that the antitumor potential did not correlate with cellular accumulation but was consistent with intracellular targeting of PDI, ER stress, and paraptotic cell death induction