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Antibacterial, Antitumor and Antiviral Compounds

#A-1220


New 2-Aryl and 2-Heterylprolines as Antibacterial, Antitumor and Anti-HIV-1 Agents: Synthesis and Structure - Activity Relationship Investigations

Tech Area / Field

  • MED-DRG/Drug Discovery/Medicine

Status
3 Approved without Funding

Registration date
11.01.2005

Leading Institute
Scientific Technological Center of Organic and Pharmaceutical Chemistry / Institute of Fine Organic Chemistry, Armenia, Yerevan

Supporting institutes

  • Scientific Technological Center of Organic and Pharmaceutical Chemistry / Molecular Structure Research Center, Armenia, Yerevan

Collaborators

  • McGill University / McGill University AIDS Centre, Canada, QC, Montreal\nInstituto de Salud Carlos III / Centro Nacional de Microbiologia, Spain, Madrid\nUniversidad Autonoma de Madrid / Centro de Biologia Molecular "Severo Ochoa", Spain, Madrid\nMcMaster University, Canada, ON, Hamilton\nUniversita degli Studi di Cagliari / Dipartamento di Scienze e Tecnologie Biomediche, Italy, Sardinia, Cagliari\nKatholieke Universiteit Leuven / Rega Institute for Medical Research, Belgium, Leuven

Project summary

Project Description.

It is well known, that in most cases, viral infections and tumor diseases attenuate the immune response of the organism, thereby activating the pathogenic micro-flora. That’s why the design and synthesis of novel antibiotics, particularly semi-synthetic penicillins and cephalosporins, having antitumor, antiviral and immunostimulating properties attracts a lot of interest.

The project deals with the synthesis and investigation of new antibiotic compounds, in search of drugs having high antitumor and antiviral activities. The development of rational approaches to the synthesis of a similar class of physiologically active compounds will be based on the comprehensive study and analysis of their structure–biological properties relationships.

The more important peculiarity of this project is the possibility to discover and investigate on novel compounds having antibacterial, antitumor and antiviral (including HIV) properties. This approach will hopefully allow to obtain information on the relationship between their chemical structural features and their biological properties.

Objectives of the Research Project

The main idea for constructing new structures lies in combination of structural fragments of known biologically active compounds. We are going to synthesize hybrid molecules containing structural elements from Penicillins, Cephalosporins (antibiotics), Sarkomycin (natural antitumor antibiotic), Amidinomycin (natural antiviral antibiotic), and Loviride (HIV-1 RT inhibitor). It is assumed that such hybrid molecules could show biological activity coming from various structural fragments.

Working for many years with such antibiotics as Sarkomycin and Amidinomycin, we studied the correlation of chemical structure and biological activity. We synthesized new derivatives of the above named groups of antibiotics showing high biological activity.

Some analogs of Sarkomicin have shown antitumor activity (on sarkoms C-180, C-37 and C-45, tumor growth inhibition ranged from 42 to 73%).

The analogs of Amidinomycin exhibit antiviral in vitro activity (when tested with influenza virus strain A/Aichi and variola vera) at a about the same level as Remantadin. It is worth mentioning that some analogs of amidinomycin show an interferon induction property too.

In last years we have also synthesized compounds belonging to the group of the 2-arylprolines, containing Loviride structural fragments. These compounds were able to inhibit the DNA polymerase activity of HIV-1 reverse transcriptase (both the wild-type and the drug-resistant mutant K103N/Y181C RTs). Their 50% inhibitory concentration (IC50) ranged from 10-3 to 10-5 M.

The class of the 2-aryl or heterylprolines allowed us to design and synthesize compounds in which structural fragments from Penicillins, Cephalosporins, Sarkomycin, Amidinomycin and Loviride might be combined. That’s why we propose to develop new effective methods for synthesizing derivatives of 2-aryl or heterylprolines.

These compounds might be considered as analogs of nucleosides in which the sugar residue is substituted by the pyrrolidine ring.

Research Methods.

1.Synthesis of new compounds.

– The method of synthesis of new derivatives of N-aryl(or heteryl)-2-pyrrolidinecarboxylic acid has been developed in our Lab and described in [3].


– We are going to study the influence of various factors on the stereochemistry and regioselectivity of processes. In particular, the influence of optically active phase transfer catalysts on an optical yield and optical cleanness.
– The methods of selective reduction of nitriles and carboxylic esters in the system of sodium borohydride – metalocomplexes will be developed.
– Synthesis of penicillines and cephalosporines will be realized by acylation of trimethylsilyl esters of 6-APA, 7-ACA and 7-ADCA with active esters of corresponding carboxylic acids.
– The methods of synthesis of new derivatives of azepins and isoquinolins will be developed.

2. The Physical-Chemical investigation of synthesized compounds and theoretical calculations.

– The single crystal X-ray investigations will be carried out on an automatic 4-circle diffractometer CAD-4 “Enraf-Nonius”.


– The NMR investigations will be carried out on Mercury 300 NMR spectrometer.
– The IR and UV investigations will be carried out on FT-IR Necsus Nicolet spectrometer and UV-VIS Specord M40 Spectrometer
– The mass-spectrometric investigations will be carried out on MX 1321A spectrometer.
– The conformational characteristics of molecules will be carried out by the molecular mechanics technique using MM3 package.
– Quantitative Structure Activity Relationship (QSAR) calculations will be used to estimate possible activity for compounds to be synthesized.

3. Biological testing of synthesized compounds.

– In vivo and in vitro testing of antitumor, antiviral and antibacterial properties of synthesized compounds.


– Testing of interaction of studied compounds with DNA of tumor and normal cells in vitro.
– Testing HIV-1 reverse transcriptase inhibition activity.

Expected Results.

The realization of this project may be important step to the understanding of mechanisms of an activity for the given class of compounds. It will be possible to plan and realize synthesis of biologically active compounds, in which antibacterial, antitumor, antiviral properties might be combined.

– It may introduce an essential contribution to the chemistry of antibiotics.


– On the basis of proposed investigations we hope to elucidate the role of the conformational flexibility of “butterfly-like” structures on HIV-1 RT Inhibition activity.
– We hope that synthesized most active compounds might be interesting for future use in medicine.
– The developed methods may be used in organic and bioorganic chemistry.
– The results of proposed investigations may be applied in pharmacology, oncology and virology.

The Realization of the Project will allow to solve the row of the problems, answering ISTC purposes:

– Reorientation of the group of scientists and specialists, earlier occupied in sphere of the weapon science, on decision of pacific human problems.


– An Assistance to decision international and national social-economic problems.
– Integration of former weapon scientist in international scientific community.

The Project will be executed by group highly qualified scientists and specialists, earlier involved in military programs of former USSR. The IFOC and MSRC NAS RA possess the necessary conditions for successful realization of the project. In different stages of the program specialists from other interested organization will be involved in project as well as. The successful execution of the project is guaranteed experience of scientists involved in project and preliminary results of the studies, a part from which is published in listed below to literature. Authors of the Project invite to cooperation scientific groups, exploratory organizations and companies from countries of European Union, USA, Japan as well as from other countries, which may be interested by our project. We offer also undertaking joint seminar and scientific studies.

Publications/presentation.

1. Martirosyan, A., Gasparyan, S., Chachoyan, A., Hovhannesyan, V., Mnjoyan, Sh., Gharibjanyan, B.: New synthetic analogs of sarkomycin. IV. Acylation amino acids and peptides with 1-phenyl-2-methyl-3-oxo-1-cyclopentanecarboxylic acid. Chemotherapy of Tumors 60, 135-140, 1993.

2. Martirosyan, A., Hovhannesyan, V., Chachoyan, A., Gasparyan, M., Jaghacpanyan, N., Gasparyan, S., Mnjoyan, Sh., Gharibjanyan, B., Camalyan, L.: New synthetic analogs of amidinomycin. I. Searches of compounds with antitumor, antiviral and interferon induction activity on a basis of modification of amidinomycin`s structure. Chemotherapy of Tumors in the USSR 56, 75-80, 1991.

3. Martirosyan, A., Gasparyan, S., Hovhannesyan, V., Mnjoyan, Sh., Aleksanyan, M., Nikishchenko, M., Babayan, G.: New method of synthesis of the 2-phenylproline and its analogs. Chemistry of Heterocyclic Compounds 4, 488-492, 2000.

4. Tamazyan, R., Karapetyan, H., Martirosyan, A., Hovhannesyan, V., Gasparyan, S.: 1-Substituted derivatives of 2-phenylpyrrolidine-2-carboxamide. Acta Crystallografica C58, o386-o388, 2002.

5. Karapetyan, H., Tamazyan, R., Martirosyan, A., Hovhannesyan, V., Gasparyan, S.: 1-Substituted derivatives of 2-aryl-5-oxo-pyrrolidine-2-carboxylic acid. Acta Crystallografica C58, o399-o401, 2002.

6. Tamazyan, R., Karapetyan, H., Martirosyan, A., Martirosyan, V., Harutyunyan G., Gasparyan, S.: 1,2,5-Substituted derivatives of 2-phenylpyrrolidine. Acta Crystallografica C60, p.o390-o392, 2004.

7. Nersesyan L.E., Garibyan D.V., et al. The role of DNA methylation in tumor cells as a primary factor in regulation and treatment of malignant formations, Medical Science of Armenia, XLIII (2), p.37-40, 2003.

8. Yu.S.Babayan, A.E.Sngryan, D.V.Garibyan et. al., Interaction of antitumor drugs mtoxantrone and ametantrone with DNA as determined from changes in circular dichroism spectra. Biophysics, 43(3), p.398-402, 1998.


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The International Science and Technology Center (ISTC) is an intergovernmental organization connecting scientists from Kazakhstan, Armenia, Tajikistan, Kyrgyzstan, and Georgia with their peers and research organizations in the EU, Japan, Republic of Korea, Norway and the United States.

 

ISTC facilitates international science projects and assists the global scientific and business community to source and engage with CIS and Georgian institutes that develop or possess an excellence of scientific know-how.

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