Laboratory of Nitrogen Compounds (LNC)

Head - Cand. of Chemical Sciences
Igor A. Kirilyuk
Phone: 8(383) 330-7387

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The Laboratory of Nitrogen Compounds LNCwas organized by professor Leonid B. Volodarsky on the basis of research group founded in 1974. Since 1998 the laboratory is headed by professor Igor A. Grigor’ev, who was simultaneously the director of the Novosibirsk Institute of Organic Chemistry SB RAS since 2002 to 2012.

The subject of research activities of the LNC originated from studies of chemistry of hydroxylamine bifunctional organic derivatives. Further evolution of these research resulted in development of original methods for synthesis of various heterocyclic compounds, oximes, nitrones and stable nitroxides.

In 1994 the Russian Federation State Premium for science and technology was awarded to three researchers from LNC for their works on “Imidazoline nitroxides”. The fruitful research activities of Laboratory research fellows allowed them to create from nitroxides a series of high technology products, “a functional spin probes”, the compounds with a set of unique properties which are relevant to various fields of science and technology. These spin probes are designed to monitor local pH values and thiol concentrations, to follow production of nitric oxide NO, formation of superoxide anion radical and other reactive oxygen species. The use of these spin probes allowed LNC in collaboration with researchers from other institutions in Russia and abroad to develop of special methods for analysis and investigation of complex molecular structures, including those related to biological samples on molecular or cellular levels, in isolated organs and tissues. Recently the examples of successful applications of these functional spin probes to noninvasive studies of physiological processes in vivo have been described; the diagnostic procedures are in developmental stage.

Besides that, a broad variety of research is being carried out in LNS currently, including development of new therapeutic agents, new functional materials for applications of organic electronic devices, molecular magnets, mediators of radical polymerization, etc. The range of research activity of LNC is still expanding.

Laboratory of Nitrogen Compounds of NIOCh SB RAS have been renowned in Russia and abroad. The majority of international conferences on EPR biological applications and/or nitroxide chemistry frequently include some scientific contributions by researchers from LNC. The Laboratory of Nitrogen Compounds was the organizer of international conferences on nitroxides in 1989 and in 2005. The LNC is more and more engaged in research collaboration with leading research groups from Russia, USA, Germany, France, Italy, Japan, etc..

The major scientific trends

• Development of the new methods for synthesis and modification of organic hydroxylamine derivatives (including nitroxides, nitrones, Alkoxyamines, etc.) and a search for the new fields of application of these compounds.
• Molecular design and synthesis of functional spin probes (i.e., those designed to monitor pH, thiols, nitric oxide NO, etc.) for investigation of various complex systems, including biological samples and models, living animals, sorbents, catalysts, etc..
• Molecular design and synthesis of specific spin labels for studies of structure and dynamics of molecular and supramolecular systems, including biological macromolecules and their complexes.
• Molecular design and synthesis of spin traps and spin probes for studies of processes involving short-living free radicals, including biogenic reactive oxygen species.
• The studies of antioxidant properties of nitroxides, hydroxylamines and nitrones; development of the therapeutic agents on the basis of the above mentioned compounds, for prevention and treatment of various pathologies, which origination and/or development is associated with reactive oxygen species; targeting of nitroxide-based antioxidants using natural and/or synthetic biologically active molecules residues.
• Development nitroxide and/or alkoxyamine mediators of free radical polymerization of vinyl monomers.
• Molecular design and synthesis of paramagnetic ligands, paramagnetic liquid crystals and similar nitroxide-containing compounds for preparations of new organic and metalocomplex magnetic materials.
• Development of nitroxide-based materials for microelectronic components, such as organic accumulators, dye-sensitized solar cells, data storage devices, etc..
• Molecular design and synthesis of new 1,1-diphosphonate-based calcium metabolism regulators and cytostatic drugs.

Scientific achievements

• The convenient scalable technologies have been developed for preparation of 1,2-hydroxyaminooxymes, 1,2-hydroxyaminoketones, N,N’-bis-hydroxyamines and similar building blocks from easily available chemicals; the utility of these blocks for synthesis of various heterocyclic systems have been demonstrated.
• As a result of extensive studies of reactivities of nitrone and imine moieties in various heterocyclic systems, the original general methods have been developed for chemical modification and synthesis of practically useful compounds.
• The original spin probes, the derivatives of stable nitroxides of imidazoline and imidazolidine series, have been developed, which EPR spectra are highly sensitive to pH changes. Based on these compounds, the methods have been developed for local pH monitoring in microvolumes of heterogeneous samples of various origin (in liposomes, polyelectrolyte pores, membrane surfaces, subcellular fractions and compartments, in extracellular media, in isolated organs and living tissues in vivo), for studies of proton transport, for studies of surface potentials of catalysts, sorbents, membranes, biomacromolecules, etc.The methods have been developed for preparation of imidazoline and/or pyrroline nitroxides with bulky substituents or spirocyclic moieties adjacent to nitroxide group; these nitroxides were shown to be resistant to reduction in biological samples.

Collaboration with:

• Pacific Institute of Bioorganic Chemistry Far-East Branch of Russian Academy of Science;
• Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus;
• Buryat State University;
• Institute of Problems of Chemical and Energetic Technologies Siberian Branch of RAS;
• JSC International research and Production holding “Phytochemistry” (Karaganda, Kazakhstan);
• Institute of Chemistry and Chemical Technology Mongolian Academy of Sciences;
• Institute of Organic Chemistry, University of Cologne (Kцln, Germany);
• Laboratory of Molecular Pharmacology, Center for Cancer Research, NCI, USA.

The major scientific trends of current researchs/Priority directions

• Basic. V.36. “Theoretical chemistry and methodology of oranic synthesis development; new methods of physic-chemical investigations”.
• Interdisciplinary Integration Projects
  • V.37: “Current problems of chemistry of materials, including nanomaterials”.
  • V.41:“Chemical problems of creation of pharmacologically active compounds of new generation”.

Current projects

• Headed or coordinated by laboratory researchers
  • RAS basic project V.36.6.8:
    • “Development of methods for synthesis of heteroatom-containing organic compounds for biomedical research and for preparation of new materials”. Headed by Prof. Igor A. Grigor’ev.
  • RFBR Projects No.:
    • 11-03-92107-ЯФ_а “Development of novel all-organic liquid crystalline nitroxide radical compounds showing strong magnetic interactions at high temperatures”. Head from RF – Grigor’ev I.A.
    • 12-03-00718-а “Development of specifically targeted nitroxides and hydroxylamines for red-ox status regulation”. Head – Prof. Grigor’ev I.A.
    • 12-03-00737-а “A new synthetic strategy for sterically hindered nitroxides based on intramolecular 1,3-dipolar cycloaddition in alkenyl nitrones”. Head – Dr. Kirilyuk I.A.
    • 12-03-31330 мол_а “Molecular design, synthesis and properties of new redox systems based on nitroxides”. Head – Mostovich E.A.
• Projects or programs in which the Laboratory is engaged
  • Federal research program RF “Physico-chemical studies of functional properties of new nitroxides and of nitroxide-based high-tech materials” headed by Prof Bagryanskaya (application 2012-1.2.1-12-000-1005-020).
  • Moscow city regional scientific programs:
    • “Development and practical application of new methods of healthcare, prophylaxis and diagnostics of cancer, infectious and another dangerous diseases”.
    • “Synthesis and studies of diphosphonic acids as a complexones for calcium metabolism regulation in atherosclerosis plaque”.
  • Interdisciplinary Integration Projects of SB RAS, V.37
    • Project No. 1 “Synthesis of functional nitroxides aimed to create new manetoactive compounds and materials” (Coordinated by corresponding member of RAS Ovcharenko V.I., ITC SB RAS).
    • Project No. 129 “A comprehensive study of soft media condition in electromagnetic field aimed to design highly efficient energy converters of new generation” (Coordinated by Dr Sci Klement’ev V.M., ILP SB RAS).
  • Interdisciplinary Integration Project of SB RAS, V.41
    • Project No. 52 “Oncogenesis of glioma and human brain reparation” (Coordinators: Dr Sci Mordvinov V.A. (ICG SB RAS) and corresponding member of RAS Krivoshapkin A.L. (ICG SB RAS).
  • RFBR Projects No.
    • 10-04-91331-ННИО_а “Nano-electrostatics of biological interfaces”. Head from RF– Academician Skulachev V.P. (MSU).
    • 12-03-01042-а “Novel synthetic methodologies for homo- and co-polymer nanostructured materials”. Head – Dr. Edeleva M.V., ITC SB RAS).
    • 12-04-01435-а “Development and application of new spin probes for in vivo EPR tomography and EPR spectroscopy of spin-labeled proteins”. Head – Bagryanskaya E. G. (NIOCh SB RAS).
   

Main publications

1. I.A. Grigor’ev. Nitrones: Novel Strategies in Synthesis, in: Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis (Ed.H.Feuer). John Wiley&Sons, Inc. 2007. Ch.2. P. 129-434.
2. И.А. Григорьев, И.Г. Иртегова, Е.Ш. Каган, И.Ю. Жукова. Электрохимия нитро-ксильных радикалов. В кн. Электрохимия органических соединений в начале XXI века. (Под ред. В.П. Гультяя, А.Г. Кривенко, А.П. Томилова). Изд-во Спутник. Моск-ва, 2008. Часть 2, глава 7. С. 315-377.
3. Л.Б. Володарский, И.А. Григорьев, С.А. Диканов, В.А. Резников, Г.И. Щукин. Имидазолиновые нитроксильные радикалы. Изд-во Наука. Новосибирск, 1988. С. 216.
4. L.B. Volodarsky, I.A. Grigor’ev, R.Z. Sagdeev. Stable Imidazoline Nitroxides, in: Biologycal Magnetic Resonance. (Eds. L.J. Berliner and J. Reuben). Plenum Press, New York. 1980. Vol.2. P.169.
5. Imidazoline Nitroxides: Synthesis and Properties, L.B. Volodarsky. Ed., CRC Press, Boca Raton, Florida. 1988. Vol.1. P. 222.
6. Imidazoline Nitroxides: Applications. L.B. Volodarsky. Ed., CRC Press, Boca Raton, Florida. 1988. Vol.2. P.162.
7. L.B. Volodarsky, V.A. Reznikov, V.I. Ovcharenko. Synthetic chemistry of stable nitroxides. CRC Press, Boca Raton, Fla. 1994. P. 225.
8. Григорьев И.А., Полиенко Ю.Ф., Войнов М.А.. рН-Чувствительные нитроксильные радикалы: структурные требования проблемы молекулярного дизайна и синтетические подходы. В: Химия ароматических, гетероциклических и природных соединений, Новосибирск: ЗАО ИПП «Офсет», 2009.
9. Григорьев И.А. Особенности химических свойств циклических нитронов и их использование в органическом синтезе. В: Химия ароматических, гетероциклических и природных соединений, Новосибирск: ЗАО ИПП «Офсет», 2009.
10. Резников В.А. Нитроксильные радикалы для координационной химии. В: Химия ароматических, гетероциклических и природных соединений, Новосибирск: ЗАО ИПП «Офсет», 2009.

Main recent (3 year) pubications

1. D. A. Morozov, I. A. Kirilyuk, D. A. Komarov, A. Goti, I. Yu. Bagryanskaya, N. V. Kuratieva, I. A. Grigor’ev. Synthesis of a Chiral C2?Symmetric Sterically Hindered Pyrrolidine Nitroxide Radical via Combined Iterative Nucleophilic Additions and Intramolecular 1,3-Dipolar Cycloadditions to Cyclic Nitrones. J. Org. Chem. 2012. DOI: 10.1021/jo3019158.
2. I. A. Kirilyuk, Yu. F. Polienko, O. A. Krumkacheva, R. K. Strizhakov, Yu. V. Gatilov, I. A. Grigor’ev, E. G. Bagryanskaya, Synthesis of 2,5-Bis(spirocyclohexane)-Substituted Nitroxides of Pyrroline and Pyrrolidine Series, Including Thiol-Specific Spin Label: An Analogue of MTSSL with Long Relaxation Time. J. Org. Chem., 2012, 77 (18), pp 8016–8027.
3. D. A. Komarov, I. Dhimitruka, I. A. Kirilyuk, D. G. Trofimiov, I. A. Grigor’ev, J. L. Zweier, V. V. Khramtsov, Electron Paramagnetic Resonance Monitoring of Ischemia-Induced Myocardial Oxygen Depletion and Acidosis in Isolated Rat Hearts Using Soluble Paramagnetic Probes, Magn. Reson. Med., 2012, 68, 649–655.
4. A. A. Bobko, T. D. Eubank, J. L. Voorhees, O. V. Efimova, I. A. Kirilyuk, S. Petryakov, D. G. Trofimiov, C. B. Marsh, J. L. Zweier, I. A. Grigor’ev, A. Samouilov, and V. V. Khramtsov, In Vivo Monitoring of pH, Redox Status, and Glutathione Using L-Band EPR for Assessment of Therapeutic Effectiveness in Solid Tumors, Magn. Reson. Med., 2012, 67, 1827-1836.
5. M. V. Edeleva, I. A. Kirilyuk, I. F. Zhurko, D. A. Parkhomenko, Y. P. Tsentalovich, E. G. Bagryanskaya, pH-Sensitive C_ON Bond Homolysis of Alkoxyamines of Imidazoline Series with Multiple Ionizable Groups As an Approach for Control of Nitroxide Mediated Polymerization, J. Org. Chem., 2011, V.76, P. 5558–5573.
6. Y.P. Tsentalovich, V.V. Yanshole, Y.F. Polienko, S.V. Morozov, I.A. Grigor’ev. Deactivation of Excited States of Kynurenine Covalently Linked to Nitroxides // Photochemistry and Photobiology. – 2011. – V.81(1). – P. 22-31.
7. S.I. Dikalov, I.A. Kirilyuk, M.A. Voinov, I.A. Grigor’ev, EPR detection of cellular and mitochondrial superoxide using cyclic hydroxylamines, Free Radical Research, 2011; 45(4): 417–430.
8. I. Kirilyuk, D. Polovyanenko, S. Semenov, I. Grigor’ev, O. Gerasko, V. Fedin, E. Bagryanskaya, Inclusion Complexes of Nitroxides of Pyrrolidine and Imidazoline Series with Cucurbit[7]uril, J. Phys. Chem. B 2010, 114, 1719–1728.
9. Morozov D.A., Kirilyuk I.A., Gatilov Yu.V., Bagryanskaya I.Yu., Bozhko J.Yu., Komarov D.A., Grigor’ev I.A., Intramolecular 1,3-Dipolar Cycloaddition of Alkenylnitrones of 4H-Imidazole Series: Synthesis of a New Nitroxide pH-Sensitive Spin Probe, Synthesis, 2010, No 2, p. 343-348.