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Organic Copper Complexes

#A-2043


Organic Copper Complexes for Radiation Protection and Cancer Therapy: From Research to Market

Tech Area / Field

  • BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
  • BIO-RAD/Radiobiology/Biotechnology

Status
3 Approved without Funding

Registration date
21.09.2012

Leading Institute
The Scientific Centre of Radiation Medicine and Burns, Armenia, Yerevan

Supporting institutes

  • Institute of Molecular Biology, Armenia, Yerevan

Collaborators

  • Wayne State University / Barbara Ann Karmanos Cancer Institute, USA, MI, Detroit\nMcMaster University, Canada, ON, Hamilton\nUniversita di Camerino / Dipartimento di Scienze Chimiche, Italy, Camerino\nUniversita di Pisa / Dipartamento di Patologia Sperimentale, Biotecnologie Medicine, Infettivologia ed Epidemiologia, Italy, Pisa\nTechnische Universität Carlo-Wilhelmina zu Braunschweig, Germany, Braunschweig

Project summary

Development of agents that protect tissues against radiation damage is currently the subject of intense research. First, current events throughout the world underscore the growing threat of different forms of terrorism, including radiological or nuclear attack that requires effective pharmaceutical products and other approaches to protect the civilian population from radiation and to treat those with radiation-induced injuries. An additional impetus for research is the need to protect surrounding healthy tissues from radiation damage during radiotherapy of cancer. Therefore, there is a need to develop drugs that could protect healthy cells leaving malignant cells susceptible - and ideally, even sensitized - to radiation therapy.
Based on the results of our recent studies on antitumor and radioprotective properties of Schiff base amino acid derivatives and their metal complexes implemented in the framework of ISTC A-1321 and A-1764 projects, several copper containing compounds were validated as hits, i.e. an active multifunctional radioprotective agents (MRPAs) and cytotoxic agents (CTAs) that merit their further studies in Drug Discovery and Development (DDD). An extended time-window effect was one of the major advantages of these copper complexes in comparison with the known radioprotectors. Selection of MRPAs was based on their protective effects detected in the animal model of ionizing radiation induced injury in case of their administration to animals prior to irradiation. Notably: as indicated by studies in vitro, no one of the selected MRPAs possesses cytotoxic effect, while selection of CTAs as potential antitumor agents was based on their cytotoxic effects towards several human cancer cell lines.
The aim of the proposed Project is to perform hit-to-lead follow-up of the selected prospective MRPAs and CTAs and to obtain marketable products for radio-protection of healthy tissues and radio-sensitization of cancers cells by in-depth assessment of their biological activities and possible adverse effects.
The study program developed to meet our objectives includes the following tasks:
Chemical synthesis and characterization of selected prospective MRPAs and CTAs. Initially, Schiff base derivates of: 1) L-tryptophan and 2-, 3- and 4- pyridinecarboxaldehydes, 2) L-histidine and 2- or 4-pyridinecarboxaldehydes, and 3) L-phenylalanine and 4-pyridinecarboxaldehyde will be synthesized using procedures successfully used in previous projects (ISTC A-1321 and A-1764). Synthesis of the copper complexes will be performed in alcohol media with the use of sodium and potassium hydroxides and copper acetate. Metallocomplexes will be characterized by melting or decomposition point, stability constants, ratio of the reacting components in complexes, molar absorbance coefficients, as well as elemental analysis and EPR, IR, and UV-Visible spectra.
Development of optimal drug delivery strategies. Based on physical and chemical properties of the synthesized copper complexes, different techniques for efficient drug delivery will be evaluated. This task will include assessment of methods for subcutaneous, oral and liposome assisted drug delivery.
Study of pharmacokinetic properties of prospective MRPAs and CTAs. Pharmacokinetic investigations will be an important part of our studies towards hit-to-lead optimization and development of effective radioprotective and anticancer preparations with the selected copper complexes as an active part.
Studies of biological activities of MRPAs and CTAs
- Assessment of toxicity of selected MRPAs and CTAs. We plan to perform basic toxicity assessment for the selected copper complexes using recently developed assay procedure of bioactive compounds, which indicates cytotoxicity as well as a wide range of pharmacological activities.
- Analysis of the activity of specific Ca2+-dependent K+-channels of erythrocytes. As sustained Ca2+ influx through store-operated, Ca2+-release activated K2+ channels is an important step in the cellular signaling pathway that leads to proliferation in a variety of cell types, including T-lymphocytes, prostate cancer cells, and fibroblasts, blockers of these K+ channels may inhibit cell proliferation and may be of potential benefit in diseases involving immune cell activation and proliferative diseases, such as cancer. We plan to measure the rate of K+ outflow from erythrocytes of animals irradiated in the presence and absence of MRPAs, or treated with CTAs.
- Analysis of the level of chromosomal rearrangements and the proliferative activity. Assessment of mentioned parameters in bone marrow cells of rats will be performed aiming to evaluate both radioprotective and cytotoxic activities of the selected metallocomplexes.
Studies of biological activities exclusive for MRPAs
- Assessment of MRPAs effects on animal survival after irradiation. Animal survival as the end point cab ne considered as the most confirmatory assay in radioprotective investigations. We plan to evaluate effect of the tested compounds on animal survival in 30 days after X-irradiation at different doses under pretreatment schemes including single or repeated subcutaneous/oral administration or liposome assisted drug delivery.
- Determination of antioxidant activity (AOA) of the synthesized compounds. The non-enzymatic AOA of the synthesized metallocomplexes against harmful reactive oxygen species will be assessed with photochemiluminescent method.
- Assessment of the effects of MRPAs on the activities of the immunocompetent cells in vivo (animal model of IR). The effects of MRPAs on phagocyte activities of neutrophils and monocytes and cytokine-production capabilities of peripheral blood mononuclear cells (PBMC) will be assessed. The assessment will be performed by 1) comparing the above mentioned parameters of PBMC isolated from the animals subjected to IR treated and non-treated with MRPAs before irradiation; 2) comparing the above mentioned parameters of PBMC isolated from human blood subjected and none-subjected to incubation with MRPAs.
- Evaluation of the potential cytoprotective effects of MRPAs by investigating the influence of MRPAs on the rate of cell death (necrosis, apoptosis) in the conditions of IR in vivo (animal model of IR) and in vitro (cell culture model of IR). We are going to analyze the potential of MRPA to protect DNA against IR-caused damage in the conditions of IR in vivo (animal model of IR). Here, rates of the genomic DNA damage and repair in the conditions of IR in the blood and bone marrow samples of rats subjected to IR in the presence and absence of MRPAs will be compared. DNA damage occurs either by direct ionization or indirectly through generation of free radicals that attack DNA, resulting in single-strand breaks and oxidative damage to sugar and base residues. Primary DNA damage may have an independent pathogenic importance and should be considered along with others categories mutational events. The DNA breaks give a measure of genome damage and the inhibition of radiation-induced DNA breaks indicates the genoprotective potential of a tested agent. Substances with genoprotective properties will be considered as the efficient MRPAs able to prevent radiation-induced cell transformation. In addition, comparison of the levels of oxidative DNA damage and DNA repair capacity in irradiated rats treated and non-treated by selected MRPAs will be also evaluated.
- Assessment of the potential genoprotective effects of MRPAs in the conditions of IR in vivo (animal model of IR). We propose to investigate the influence of MRPAs on the rate of cell death by apoptosis and necrosis, which highly increase under the influence of IR. Here the rates of both necrosis and apoptosis in the conditions of IR in vivo (animal model of IR) and in vitro (cell culture model of IR) in the presence and absence of MRPAs will be compared. In particular, it is planned to compare the rates of necrosis and apoptosis in PBMC isolated from the rats and human blood subjected to IR in the presence and absence of MRPAs.
Studies of biological activities exclusive to CTAs
- Evaluation of the potential cytotoxic effects of CTAs (influence on the rates of apoptosis and necrosis) on malignant cells in situ (blast cells of leukemia patients). The most clinically important characteristic of an effective chemotherapeutic is its potential to induce malignant cell death. On this stage of the proposed investigations we are going to isolate the abnormal immature white blood cells (blasts) from the blood of patients with different types of leukemia and to compare the rates of apoptosis and necrosis of these cells in the presence and absence of CTAs.
- Assessment of the possible side-effects of CTAs on healthy cells including suppression of the activities of immunocompetent cells, cytotoxicity, and genotoxicity (DNA damage and repair). Another clinically important feature of chemotherapeutic agents includes reduced immunosuppressive, cyto- and genotoxic effects regarding non-malignant cells. Thus, we propose to test the immunosuppressive, geno-, and cytotoxic effects of selected CTAs towards the normal blood cells.
The results obtained during the implementation of the proposed project will support the introduction of new multifunctional radioprotectors in radiation medicine. The efficiency and multifunctionality of the suggested radioprotectors will be proved by combination of various in vitro, in vivo and in situ methodological approaches.
Another important result of the proposed study that may be applied in clinical oncology will represent introduction of new antitumor agents with low side effects, targeting, particularly, leukemic cell.
In compliance with the aims set forth by ISTC, implementation of this project will facilitate the integration of Armenian scientists into the international scientific research community, use their knowledge and experience gained in closed laboratories of defense profile for solution of peaceful medical and biological tasks. Together with weapon scientists making up to 46.15% of the total number of participants, the active young scientists composing 18% will promote the successful Project fulfillment.


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