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Radioprotectors and Immunomodulators for Protection against Radiation

#3311


Development of New Generation of Radioprotectors, Immunomodulators, and Radiation Sensitizers for Human Protection Against Ionizing Radiation and Efficiency Improvement of Radiotherapy of Malignant Cells

Tech Area / Field

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

Status
3 Approved without Funding

Registration date
28.06.2005

Leading Institute
VNIIEF, Russia, N. Novgorod reg., Sarov

Supporting institutes

  • St Petersburg State Chemical-Pharmaceutical Academy, Russia, St Petersburg\nMoscow State University / Department of Chemistry, Russia, Moscow

Collaborators

  • University of Maryland / School of Medicine / Department of Radiation Oncology, USA, MD, Baltimore\nDurham University, UK, Durham\nUniversity of Cincinnati / Department of Cell Biology, Neurobiology and Anatomy, USA, OH, Cincinnati\nBattelle Energy Alliance LLC (BEA) / Idaho National Laboratory, USA, ID, Idaho Falls

Project summary

The protection of humans and animals from the influence of ionizing radiation (IR) is one of the most actual problems of radiation biology and medicine. This problem has become especially relevant recently owing to broad practical use of atomic energy, active implementation of radioactive materials and radiation technologies in medicine and different areas of science and engineering, development of the outer space etc.

The radioprotectors, immunomodulators and radiation sensitizers are means of antitumoral radiation therapy. Substances of these classes promote the withdrawal of radioactive nuclides from the organism, the increase of the body resistance to the effect of ionizing radiation (IR) and provide normalization of the immune, endocrine and nervous system under conditions of professional and therapeutic effect of IR.

Despite the intensive research in our country and abroad aimed at finding chemical means of protection from ionizing radiation for humans and animals, the outcomes remain rather retiring [1-10]. There are only a few substances, which can be considered potentially suitable for practical use, and none of them meet all the requirements set for the medicines.

The known radioprotectors comprise mercaptoalkylamines (Cysteaminum, Cystaminum, aminethylisothiouronium), indolilalkylamines (Mexaminum) and some other substances related to heterocyclic compounds with sulfhydric groups. Natural and synthesized immunomodulators (sodium nucleate, inosinoplex, levomisol, zymosan) [7,8,11,12] are used in treatment of a human radiation sickness syndrome. So, high radioprotective efficiency on mammals is exhibited by biogenic amines (serotonin, epinephrine and their derivative) [13-15]. The influence of radioprotectors is directed first of all on protection of the marrow and other hemopoietic tissues.

It was found out that even the most effective synthesized compounds of these classes, for example an organic radioprotector called Cystaminum, either does not have a demanded radioprotective effect, or when used in advisable doses causes the development of a number of toxic or severe side effects. In the overwhelming majority of the previously conducted research the primary goal was to obtain drugs of preventive character (to be introduced before irradiation), and not of the medical character (to be introduced after the irradiation).

Thus, the purpose of the proposed project is the development of new efficient and low toxic means of protection of the human organism from the influence of the ionizing radiation (radioprotectors and immunomodulating compounds) and means to improve the efficiency of radiotherapy on the tumor cells (radiation sensitizers).

To reach the goal of the Project we will resolve the following problems:

  1. Development of effective and ecologically safe technologic methods to synthesize new groups of highly active and low toxic radioprotective drugs of a new generation;
  2. Synthesis of a broad spectrum of unique replaced thio- (oxo-)pyrimidines, their tia-, oxa- and deaza- clones, of heterocyclic systems condensed with them, glycosides and products of their transformation under the influence of the nucleophilic agents;
  3. Determination of a fine structure of target compounds, their physical characteristics and reactivity;
  4. Modeling of metabolic transformations of target compounds in a human organism;
  5. Determination of toxicity of target compounds;
  6. Determination of radioprotecting, anti-oxidant, immunomodulating and radiation sensitizing activity;
  7. Determination of approaches to find the mechanism of radioprotective and radiation sensitizing effect of the obtained compounds and its connection with the electronic structure of a molecule.

Expected results:
  1. From a broad range of new thioxo(oxo)-1,3-hetero(aza, tia, oxa and deaza)azines and the systems condensed with them, which will be synthesized within the Project, there will be selected 3-5 most promising radioprotectors, immunomodulators, anti-oxidants, or radiation sensitizers to be introduced into the clinical practice.
  2. Production of a necessary amount of the selected compounds for further “pre-clinical” study.
  3. Working out of a system of express-selection of radioprotectors and their directed synthesis on the basis of quanta-chemical calculations for molecule and electron structures of the compound.
  4. Determination of approaches to creation of drug dosage forms of the elaborated compounds.
  5. Working out of methods to determine the quality, quantity and standards for the selected most promising compounds and their drug dosage forms.
  6. On the basis of the research performed standard and technical documentation for patenting and introduction of the elaborated compounds into the industrial production will be prepared.

The compounds elaborated within the Project will meet the following requirements:
  1. High efficiency, low acute toxicity and absence of side effects.
  2. High bioavailability (degree of infiltration of the drug in the blood) and optimal physicochemical characteristics for creation of the drug dosage forms.
  3. A low number of stages, ease of reproduction on a larger scale, and ecological safety of synthesis methods.
  4. Use of easy-available, cheap and non-toxic raw materials.
  5. Long storage time of the synthesized drugs (not less than 2 years).
  6. The optimal physicochemical characteristics for creation of the drug dosage forms.
  7. Patentability of the obtained compounds and synthesis methods.

Perspectives in the development and commercial implementation of the outcomes of the Project.
  1. As a result of the work within the Project, 3-5 of the most efficient non-toxic potential radiaprotectors, antioxidants, immunomodulators and radiation sensitive substances will be selected from a broad range of synthesized compounds;
  2. Production of a necessary amount of the selected compounds for their further “pre-clinical” study;
  3. Carrying out of “pre-clinical” tests and pharmaceutical research aimed at examining the influence of synthesized compounds on hemopoiesis, bone formation, CNS and other kinds of a biological potency;
  4. Development of methods to establish the quality, the amount and standards for the synthesized compounds;
  5. Development of drug dosage forms of the compounds having greatest prospects by the results of the pre-clinical tests;
  6. The created drugs will be passed to clinics to undergo clinical tests;
  7. Preparation of necessary documents to introduce the drugs into the industrial and clinical practice.


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