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Identification of New Pharmacology Active Substances

#B-434


The Development of New Methods of Purposeful Search for Pharmacologically Active Substances Based on Radiolysis Data for Natural Compounds

Tech Area / Field

  • MED-DRG/Drug Discovery/Medicine
  • BIO-CHM/Biochemistry/Biotechnology
  • CHE-RAD/Photo and Radiation Chemistry/Chemistry

Status
8 Project completed

Registration date
30.11.1999

Completion date
28.09.2004

Senior Project Manager
Evstyukhin K N

Leading Institute
Belarussian State University / Institute of Physical Chemical Problems, Belarus, Minsk

Supporting institutes

  • National Academy of Sciences of the Republic of Belarus / Institute of Radiation Physics and Chemistry Problems, Belarus, Minsk, Sosny

Project summary

The Republic of Belarus is now in a very complicated economical situation, and this is, under many aspects, the principal cause of decrease in the standards of living and deterioration of the main health indices of the population.

In the last decade, an overall sickness rate increase of ca. 12% has been noted, and much higher values have been registered for such socially significant diseases as these of nervous system – by 60.5%, endocrine system – by 33.9%, blood circulation system – by 27.8%, and cancer – by 16% [1].

One of the causes of the deterioration of human health is poor availability of medicinal products for health establishments and population. So, according to a report from the Ministry of Health Care, the demand for imported drugs is covered to 20-25%, and that for home-produced drugs – to 30-35%.

To improve the situation, steps should be undertaken towards the development of our own efficient pharmaceutical products and their introduction into medical practice. However, the actual economical state of the country does not allow to finance such work in full. It is generally known that the costs of creation of a new drug in developed countries of the world, depending on its application field and the approach used, make one to several tens of million dollars, which, as a rule, are compensated within several years.

The costs of creation of new pharmaceutical products depend substantially on methods of search for pharmacologically active substances (PAS) chosen. Until present, the discoveries of new PAS were made mainly spontaneously, as a result of accidental observations, lucky findings, or extremely labor-consuming screenings of multitude of compounds. Such approaches, due to their low efficiency, are very expensive. So, the success rate in a screening to find out a highly efficient drug compound is of the order of 1: 10,000 [2]. Although the screening has played a very positive role in the search for PAS, the poor profitability of this method has now become evident. Actually, better perspectives are attributed to rational approaches to the search for PAS, based on information concerning the structure of endogenous metabolites, ferments, receptors, the nature of biological disturbances, and mechanisms of pathophysiological processes taking place in a given disease.

Free-radical processes are known to play an important part in normal or pathological functioning of an organism. By now, it has been reliably established [3] that activation of free-radical reactions and, in the first place, of lipid peroxidation (LPO), is the cause of a number of various diseases. The increase in radiation background in several regions of world after the Chernobyl disaster led to an increase of number of cases caused by radiation-induced free-radical processes taking place in an organism.

For prevention and treatment of diseases of free-radical ethiology, inhibitors of free-radical processes, in particular, antioxidants such as -tocopherol, ionol, probucol a.o. are extensively used. At the same time, the approach taking into account just homolytic oxidation of biological objects, which is commonly used in the search for free-radical reaction inhibitors, has been exhausted under many aspects. To obtain more efficient inhibitors, detailed information on their interactions with radicals of various types is necessary. The use of various methods and techniques of radiation chemistry is very promising for obtaining information of this kind [4].

Purpose of the Project is the development of new methods of purposeful search for pharmacologically active substances based on radiolysis data for natural compounds.

Novelty of the Project

For the first time, the selection of free-radical reaction inhibitors will be made not only taking into account the ability of compounds under study to suppress the lipid peroxidation processes in the cell membranes, but also according to their efficiency as free-radical fragmentation inhibitors in biologically important compounds. The necessity of search for such type of compounds derives from the fact we established in the course of our radiolysis studies of aqueous solutions of carbohydrates [5], nucleosides [5, 6], amino acids [5, 7, 8], and lipids [9, 10], namely that, in addition to oxidation processes, the free-radical fragmentation processes play an important part in the damage of biologically important substances.

Practical importance of the Project

From the results that will be obtained, scientifically grounded methods of selection of pharmacologically active substances will be developed, and this will allow to reduce time and costs for creation of new drug products significantly. The above can be confirmed by the data obtained by the authors on inhibition of free-radical reactions of different types by various phenol derivatives. Thus, it has been shown that ortho-substituted phenols are more universal free-radical reaction inhibitors than their functional analogues like ionol, probucol, and other known antioxidants. The perspectivity of their use in medical practice has been demonstrated in biological activity studies carried out in animals, as well as on model systems in vitro. So, it has been established that the substance F3 (a pyrocatechol derivative) is an efficient bio-oxidant and possesses pronounced anti-hypoxy and anti-inflammatory properties [11]. Its water-soluble analogue F54 – an efficient bio-oxidant – possesses anti-viral [12] and nootropic activities superior to those of Pyracetam in many parameters. A number of o-substituted phenol derivatives we synthesized (F3, F37, F46, F53, F54 a.o.) manifest protective effects in models, revealing, in particular, anti-inflammatory and analgetic properties.

The bifunctional phenol derivatives that we were first to synthesize have undergone trials at the National Cancer Institute (USA) and have been found to possess the ability to inhibit the cancer cell growth efficiently.

Using the above approaches, we have developed an anti-herpetic product - Butaminophen - which is not inferior in its activity to Acyclovir being, at the same time, prepared from cheap and readily available raw materials. The introduction of Butaminophen into medical practice will allow to spare hundreds of thousand dollars, which are thus far spent for purchase of its foreign analogue Zovirax.

The research scientists and engineers taking part in the Project possess the relevant knowledge in physics and accelerator technology, radiation chemistry and chemical technology, free-radical chemistry, synthetic organic chemistry, pharmacology and pathophysiology. The Project Manager is a leading specialist in the field of radiation chemistry. He performed his research work in numerous laboratories of the world (Basel University, Switzerland; Illinois University, USA, a.o.) and maintains fruitful scientific contacts with foreign scientists.

In the course of implementation of the Project, information exchanges with the Collaborator and discussions of the results obtained are suggested. On this basis, comments to the report will be given. Moreover, within the framework of the Project, studies of kinetic characteristics of various free-radical reactions are planned, using the Collaborator’s methodologies and equipment, as well as joint scientific workshops with the Collaborator.

The implementation of the Project will allow to use knowledge and experience of scientists and engineers formerly connected with the development and production of weapons to solve theoretical and experimental problems connected with the development of preparative methods for chemical compounds having valuable medical properties, that is, to turn them towards peaceful activities.

The results obtained in the course of work on the Project will broaden the actual views of free-radical damage mechanism in biosystems and their chemical correction. This will contribute to the progress in development of the promising new trend formed at the meeting-point of Chemistry, Biology and Medicine, and stimulate scientific cooperation between the Project Participants and foreign researchers working in this field. The approaches to the purposeful search for PAS developed in the course of the Project implementation, as well as the synthesized PAS themselves will be original, and hence proprietary, and this points to the commercial importance of the Project. If the work on creation of drugs on the basis of novel PAS will continue, we expect to obtain medicaments competitive on the world market. Their introduction into medical practice will allow to spare important means (millions of dollars), and the Project Investor will have the advantage of privileged acquisition of license for the new products.

REFERENCES

[1] The State Program “Health”. The Ministry of Health Care of the Republic of Belarus. Minsk, 1998.

[2] Vladimirov, V.G., Krasil’nikov, I.I., and Arapov, O.V. Radioprotectors: Structure and Function/ Ed. by Vladimirov, V.G.. Kiev, Navukova dumka Publ., 1989.

[3] Halliwell, B. And Gutteridge, J.M.C. Free Radicals in Biology and Medicine. 3th Ed. Oxford, Clarendon Press, 1999.

[4] Pikaev, A.K. Modern Radiation Chemistry. Radiolysis of gases and Liquids. Moscow, Nauka Publ., 1986.

[5] Von Sonntag, C. The Chemical Bases of Radiation Biology. London, Taylor and Francis, 1987.

[6] Akhrem, A.A., Petryaev, E.P., Moshchinskaya, S.V., Timoshchuk, V.A. and Shadyro, O.I. Dokl.AN SSR, 1987, 296, No.4, 872.

[7] Garrison, W.M. Chem.Rev., 1987, 87, 387.

[8] Shadyro, O.I., Sosnovskaya, A.A., and Vrublevskaya, O.H. Khimiya vysokikh energii, 1999, 33, No.2, 94.

[9] Edimicheva, I.P., Kisel, M.A., Shadyro, O.I., Vlasov, A.P., and Yurkova, I.L. Int.J.Radiat.Biol., 1997, 71, No.5, 555.

[10] Muller, S.N., Batra, R., Senn, M., Giese, B., Kisel, M, and Shadyro, O.I. J.Am.Chem.Soc., 1997, 119, 2795.

[11] Shadyro, O.I., Shilov, G.M., et al., USSR Author’s Certificate No. 1827259, Bulleten’ izobretenii, No.29, 1993.

[12] Petrikevich, D.K., Timoshchuk, V.A., Shadyro, O.I., Andreeva, O.T., Votyakov, V.I., and Zhelobkovich, V.E. Khim. farm. zhurnal, 1995, No.12, 32.


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