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Antitumor and Radiomodifying Organometallic Copper Complexes

#A-1764


Novel Radiomodifying and Antitumor Agents: Research and Development of New Radiomodifying and Antitumor Organometallic Copper Complexes

Tech Area / Field

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

Status
8 Project completed

Registration date
11.08.2009

Completion date
02.08.2013

Senior Project Manager
Melnikov V G

Leading Institute
Research Center of Radiation Medicine and Burns, Armenia, Yerevan

Supporting institutes

  • Institute of Molecular Biology, Armenia, Yerevan

Collaborators

  • Technische Universität Carlo-Wilhelmina zu Braunschweig / Institut für Pharmazeutische Chemie, Germany, Braunschweig\nWayne State University / Barbara Ann Karmanos Cancer Institute, USA, MI, Detroit\nMcMaster University, Canada, ON, Hamilton\nUniversita di Camerino / Dipartimento di Scienze Chimiche, Italy, Camerino\nMedical University of Vienna / Institute of Pharmacology, Austria, Vienna

Project summary

In today's heightened nuclear/biological/chemical threat environment, there is an increased need to have safe and effective means to protect not only special high-risk service groups, but also the general population at large, against the health hazards of unintended ionizing radiation exposures. However, despite a substantial amount of research carried out in the field of chemical radioprotection during the last few decades, no safe and ideal synthetic radioprotectors are available to date and not a single compound has emerged so far as an effective non-toxic radioprotector for practical purposes.

Due to the variety of functions and the relevance in perse redox processes in biological systems metal ions are considered to be promising agents for development of metal-containing drugs for therapeutic and diagnostic applications in medicine. Taking into account the role of essential metalloelements in tissue maintenance and functions as well as the roles of essential metalloelement-dependent enzymes in responding to injury, metal-containing compounds are considered as worth for screening of effective radioprotectors and cytoprotectors in case of both accidental exposure and indicated tumor radiotherapy.

Copper is an essential trace element and plays a crucial role in living systems, performing a wide variety of functions in the active site of proteins and enzymes involved in metabolism. Copper serves as a cofactor in enzymes involved in cellular energy generation, free radical detoxification, connective tissue production, iron mobilization, and neurotransmission. Recognizing that the small molecular mass copper chelates may be used as physiologically and biochemically relevant transport forms of copper, small molecular mass copper chelates have been used to successfully treat many animal models of inflammation, ulcer, wound healing, pain, seizures, neoplastic diseases, carcinogenesis, mutagenesis, diabetes, ischemia/reperfusion injury, cardiovascular diseases, as well as ultraviolet and lethal ionizing irradiation injury.

According to scientific literature data as well as proceeding from our own experimental results obtained during the implementation of ISTC A-1321 Project “Radioprotective and Radiorecovery Cu and Mn Nicotinyl-L-Amino Acid Schiff Base Chelates” (M.H. Malakyan, Project Manager), chelates of Cu(II) with Schiff base amino acid derivatives among other transition metalloelement chelates of N-substituted amino acid Schiff bases studied as the part of our earlier funded ISTC A-361 Project (Title: “Synthesis of New Ethyl Esters and Salts of Transition Metals of N-substituted Amino-Acid Schiff Bases: Study of the Antioxidant and Radiation Protective Activities”) reveal significant radiation protection and radiation recovery activities and cause rapid recovery of immunocompetence. An extended time-window effect was one of the major advantages of these copper complexes in comparison with the known radioprotectors.

The results of the clonogenic assay and bystander assay showed a strong radioprotective effect and abolition of the bystander toxic effect by Cu(II)(Nicotinyl-L-Tyrosinate)2 and Cu(II)(Nicotinyl-L-Tryptophanate)2 synthesized and studied during the A-1321 ISTC Project. These data suggest that these Cu(II) chelates are potentially useful for protecting normal cells against toxic effects of radiation. Since the ability of drug to prevent radiotherapy-induced toxicity without affecting the antitumor efficacy has a potential to enhance the therapeutic benefit for cancer patients without increasing their risk of serious adverse effects, data obtained with the above mentioned copper complexes are attractive for investigation of these and other copper organic chelates in oncology. At present, many copper complexes are defined as promising anticancer agents. Moreover, it is reported that co-administration of Cu(II) chelates decreases life threatening Cisplatin [PtII(NH3)2(CL)2]-induced side effects consistent with serious necrotizing and immune-mediated inflammatory disease.

All these results provide support for preparation of this Project proposal devoted to synthesis of new organometallic copper complexes and biological evaluation of the compounds obtained as radiomodifying and antitumor agents.

In the frames of this proposed Project we plan to perform the following research:

  • Chemical synthesis and characterization of Schiff base ligands derived from 2-pyridinecarboxaldehyde (Picolinaldehyde), 3-pyridinecarboxaldehyde (Nicotinaldehyde), or 4-pyridinecarboxaldehyde (Isonicotinaldehyde) and L-Phenylalanine, L-Histidine, or L-Tryptophan aromatic L-Amino acids. Chemical synthesis and characterization of Cu(II) chelates of the Schiff bases obtained. Study of their structure and other physical-chemical parameters including: dissociation constants, melting or decomposition points, stability constants, ratio of the reacting components in complexes, molar absorbance coefficients, elemental analyses and NMR, UV-Visible, and IR spectroscopy.
  • Study of anti-radical and anti-oxidant reactivity of picolinyl-, nicotinyl-, and isonicotinyl-L-amino acid copper chelates in vitro using: 1) photochemiluminescent method of analysis; 2) DPPH assay; 3) Thiobarbituric Acid assay; and measuring: 4) Anti-hemolytic activity; 5) SOD-mimetic activity; 6) CAT-mimetic activity.
  • Investigation of the mode and DNA binding behaviors of the copper. Study of “DNA-ligand” interaction.
  • Evaluation of albumin binding properties of the novel copper organic complexes applied to a column with Sefadex G25.
  • Analysis in vitro of antitumor and tissue-specific activity of new compounds using human cell lines of various tissue origins (blood, liver, kidney, cervix, breast, etc.).
  • Study of genotoxic activity of new compounds using micronucleus (MN) induction, cytokinesis-block method.
  • Analysis in vitro of radio-modifying (protecting and sensitizing) effects of new compounds.
  • Determinations of radioprotective activities of copper (II) chelates in vivo taking into consideration different routes of administration to animals, time of treatment before irradiation and radiation dose variations. Determination of cytogenetic parameters of bone marrow cells, immunological, hematological, biochemical, and biophysical indices of animal blood on days 1, 7, 14, 21 and 28 after irradiation. The following indices will be determined:
    • The level of chromosomal re-arrangements and the proliferative activity of bone marrow cells.
    • Total levels of circulating immune complexes in blood, IL-1, PGE2, Bax /bcl-2: Bcl-2, C1q, C3b.
    • Hematocrit, hemoglobin content, as well as erythrocyte, leukocyte, and platelet counts and blood clotting time.
    • Lipid peroxidation in blood plasma and erythrocyte membranes.
    • Content of the middle-molecular-mass peptides in animal blood plasma.
    • SOD-, and CAT- activity in erythrocytes and blood plasma.
    • Integral antioxidant capacity of both lipid-soluble and water-soluble non-enzymatic antioxidants of blood plasma.
    • Melting parameters of DNA isolated from liver of rats.
    • K+ outflow rate from erythrocytes and erythrocytes membrane potential.
The described studies will be performed in the Scientific Centre of Radiation Medicine and Burns of the Ministry of Health of the Republic of Armenia and in the Institute of Molecular Biology of NAS of the Republic of Armenia. These organizations have scientific staff formerly engaged in the programs of USSR Ministry of Defense. During the fulfillment of the earlier funded ISTC A-361 and A-1321 Projects, outcomes of which became the basis for preparation of this Project Proposal, the self-sufficient scientific-research teams of experienced scientists and qualified young specialists were formed in the afore-named scientific organizations. During the last years in the course of implementation of A-361 and A-1321 ISTC projects a number of new chemical compounds and substances of natural origin were identified as agents with radioprotective properties. As a result of these investigations the application for patenting the invention entitled as “Coordination complexes of Cu(II) with Schiff Bases derived from nicotinaldehyde and amino acid L-Tyrosine or L-Tryptophan having a radioprotection activity” is presented to Agency on Intellectual Property of Armenia (Application is registered under the number 09-041. All the costs for the procedure of patenting are covered on the financial means of ISTC 0442 Agreement).

Studies in animals will be performed according to the regulations described in the Guidance for Ethical Animal Care and Use in Biomedical Research adopted at the Ministry of Health, Republic of Armenia. Animal care and handling will be done according to the guidelines set by Committees on Bioethics acting at the Scientific Centre of Radiation Medicine and Burns and in the Institute of Molecular Biology.

Funding of this Project and fulfillment will allow researchers at our research facilities to use knowledge and experience gained in formerly closed laboratories of military defense, to pursue solutions of peacetime medical and biological research problems. Weapons scientists make up 53.8% of the total number of Project participants. The proposed study will facilitate the integration of Armenian scientists into the international scientific research community.


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