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Onco- and Radioprotectors

#A-1771


Development and Study of New Onco- and Radioprotectors on the Base of Biologically Active Compounds of 1,3-Diazaadamantane in Experiment

Tech Area / Field

  • BIO-RAD/Radiobiology/Biotechnology
  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry
  • MED-DRG/Drug Discovery/Medicine

Status
3 Approved without Funding

Registration date
18.08.2009

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

Supporting institutes

  • Yerevan Institute "Plastpolymer", Armenia, Yerevan\nScientific Technological Center of Organic and Pharmaceutical Chemistry, Armenia, Yerevan

Collaborators

  • University of Murcia / Faculty of Medicine-Dentistry / Laboratory of Experimental and Clinical Radiology, Spain, Murcia\nThe Cleveland Clinic Foundation / Lerner Research Institute, USA, OH, Cleveland\nThomas Jefferson University / Jefferson Kimmel Cancer Center, USA, PA, Philadelphia

Project summary

The project aim is complex study of biological consequences of ionizing radiation influence and biologically active compounds of 1,3-diazaadamanatane of various dose ratio in an experiment which will serve as a basis for creation of effective radioprotectors.

There is no modern oncology without chemotherapy and radiotherapy, however, these two methods of treatment have adverse reaction. It is well known that the main inhibitor in chemotherapy of malignant neoplasms is high toxicity of antitumor preparations. Radiotherapy is accompanied by early and delayed complications, this method is rather traumatic for healthy tissues and cells getting in field of radiation or laying near them. Radiation injuries can be observed not only in case of radiation therapy, but also in case of production connected to atomic energy, in case of radiation accidents and terroristic acts, in case of production of radiopharmpreparations and medical staff engaged in radionuclide diagnostics and angioplasty. In its turn one of the main delayed consequences of biological action of radiation (stochastic effects) is occurrence and development of malignant neoplasms. Taking into account the fact that either tumor disease, or radiation disease in majority are accompanied by decrease of immune reactions of an organism, activation of pathogenic micro-flora and development of acute infectious diseases, development of new preparations obtaining antitumor, radioprotector, immune-stimulating properties and biological assessment of combined action of chemical and physical factors is one of the actual tasks of modern medicine.

Study of mutual actions of various harmful factors is very difficult task because of unpredictability of effects from different factors, possibility of their synergistic interaction in biological objects. In the proposed project it is planed the assessment of biological consequences of ionizing radiation and chemical agents action, i.e. 1,3- Diazaadamanatane compounds possessing antitumor and antibacterial properties.

In modern medicine preparations based on adamantane derivatives (remantadin, amantadin, tromantadin, kemantane, etc.) are widely applied. 1,3- Diazaadamanatane derivatives differing from adamantane by availability of two nitrogen atoms in carcass, also show different biological activity. Studies carried out in STCOPC (former Institute of Fine Organic Chemistry) during many years showed that some of 1,3- Diazaadamanatane derivatives possess antibacterial, antitumor and antioxidant activity compared with activity of well-known antioxidant – ionol. The project is supposed to give an answer to the question what is the effectiveness of studies carried out earlier and 1,3- Diazaadamanatane compounds synthesized again in irradiated organism of an animal. Experimental researches at first stage of new 1,3- Diazaadamanatane antitumor and antibacterial compounds work will then allow to carry out purposeful search and to develop new radioprotectors.

The main orientation while our search of new radioprotectors will serve high effectiveness at low toxicity. In this connection of great interest is introduction of various indols of lipophilic adamantane fragments into molecules. It is well-known that introduction of adamantile radicals into known preparations modifies their biological activity changing or often intensifying it. It is, first of all, connected to the fact that spatial building, lipophilicity of compounds containing adamantane carcass creates favorable conditions for transportation of molecules through biological membranes.

In this project it is supposed: synthesis of new indolylalkylamines that contain fragments of 1,3-Diazaadamantane, obtainment of new radioprotector polymer systems; combination of radioprotective means with the factors that increase the general non-specific resistance of an organism. It is planed to develop a system of express-choice of radioprotectors and their aimed synthesis based on methods of computer modeling. Inclusion of radioprotector fragments into a structure of non-toxic polymers will allow not only to prolong their action, but to decrease the used preparations doses, to reduce their toxicity and adverse reactions as well. Moreover, it is not excluded that having their own biological activity, polymers performing cooperative interactions with a radioprotector, may significantly increase prophylactic efficacy of the preparations. In order to achieve the project goals works on solution of main tasks are planed: synthesis of new biological active 1,3- Diazaadamanatane compounds, including polymer ones, study of their properties, medical-biological studies in an experiment in animals, synthesis of new onco- and radioprotectors. In order to save time for screening and to carry out the aimed synthesis the researches will be conducted in three stages: theoretical QSAR calculations by means of BIOGRAFX, DRAGON, PYMOL and AUTODOCK software, based on radioprotector activity applied in clinical practiceof well-known radioprotectors; selection from lots of virtual structures of more perspective from the point of view of prognosis structure for synthesis; and biological testing of obtained compounds.

In the frameworks of the present project it is supposed to use radioprotective means for prophylactics and treatment of radiation injuries in the complex with measures of biological stimulation of general non-specific resistance of an organism. For successful realization of the project tasks the composite authors will use computer modeling. The establishment of correlation between structure, physical-chemical properties and medical-biological characteristics of perspective radioprotectors will allow to realize directive synthesis of indole derivatives and polymers with necessary medical-biological properties.

The results of the work on the proposed project will have important practical significance in creation of new biological active compounds and highly effective radioprotectors. The obtained results of radiobiological researches will add and specify existing presentations on mechanisms of both radiation injuries, and mutual action with biological active compounds in case of oncologic diseases.

Development, experiments and implementation of new radioprotectors are not only actual scientific problem, but it has a great practical meaning as well, including Scientific Center of Radiation Medicine and Burns, where supervision of inpiduals who participated in liquidation of the consequences of the Chernobyl NPP and exposed in the accidental conditions at the Mayak Production Association under Chelyabinsk, as well as at the productions with usage of resources of ionizing radiation is carried out. Scientific Center of Radiation Medicine and Burns (WHO Collaborating Center) is leading institution in Armenia on diagnostics and treatment of radiation injuries.

Project methodology includes both well-known and developing by the project developers methods of synthesis and medical and biological assessments of new biological active 1,3- Diazaadamanatane compounds.

In accordance with ISTC goals the following tasks will be realized on performing the present Project: re-orientation of the activity of scientists engaged previously in defense activity to solution of Public Health problems of persons having close contact with sources of ionizing radiation.

In the frames of this project the role of the foreign Collaborators consists in joint discussion of the results and information exchange in the process of Project implementation.


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