Laboratory of Medicinal Chemistry (LMCh)

 

Department of Medicinal Chemistry

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Laboratory of Medicinal Chemistry (LMCh)

(up to 2004 г - Laboratory Wood Chemistry and Biologically Active Compounds - LFC&BAC)

Head - Doctor of Chemical Sciences, Professor Shults Elvira Eduardovna

Phone: 8(383)330-85-33,
internal phone: 2-35
email:This email address is being protected from spambots. You need JavaScript enabled to view it.

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The laboratory was founded in 2004 in the staff of Department of Chemistry of Natural and Biologically Active Compounds.

 

The major scientific trends

• Investigation of chemical composition of several plants of Apiaceae, Asteraceae and Fabaceae family as the goal for investigation of sources of sesquiterpene lactones, coumarins and saponines.
• Chemistry of plant alkaloids, development of methods of synthesis and functionalization of isoquinoline, pyridine, diterpenoid and norditerpenoid alkaloids, investigation of their transition metal-catalyzed transformations.
• Palladium catalyzed elaboration of coumarins and their derivatives, synthesis of heterocyclic analogs of combretastatins.
• Development of new synthetic transformations of sesquiterpene lactones and high terpenoids. Synthesis of nitrogen containing heterocyclic compounds• in the labdane, lupane and abietane series. Pd-catalyzed cross-coupling reaction of methylene lactones with aryl halides, 5-bromouracil and iodouridine derivatives.
• Development and production of new agents for treatment of particularly dangerous diseases.

Scientific achievements

• Original methods for isolation of practically important compounds - lappaconitine, elatine, isoalantolactone, peucedanin, peoniflorine, lambertianic acid, pinusolide, flomisoic acid and quinopimaric acid from renewable resources have been development.
• Directed synthetic transformations of plant terpenoids (furan-type labdanoids, levopimaric acid, betulin and betulonic acids), coumarins and alkaloids are carried out.
• Some regularities in the Diels-Alder reaction of diterpenoids – levopimaric and lamdertianic acids and their esters have been carried out. Original approaches to the heterocyclic compounds containing perhydronaphtho[1,2-h]quinazoline and hexahydro-3,6-mathanoindole structural fragments by selective transformations of abietan-type diterpenoids are proposed. Heterocyclic labdanoids of new structural types, with indole, isoindolone, carboline, 3-terpenyl-substituted pyrrol-2(5H)-one, N-substituted maleimides moities, as well as compounds of 8,12-epoxylabdanoid srtuctures have been developed by explored the furan ring selective oxidative methods, selective cycloaddition reactions and intramolecular Diels-Alder approach. The oxidative Heck reaction and Gold-catalyzed reactions, allowing to carry out the specific transformations furanoditerpenoids have been studying. The first synthesis of acetylenic derivatives of labdane type diterpenoids lending to the development of a new series of biohybrids have been achieved.
• Original synthetic approached to aryl substituted polyhydroxynaphtho- and anthraquinones, included compounds with diterpenoid structures were developed. These compounds were characterized as a novel group of selective inhibitors of human immunodeficiency virus reverse transcriptase; the moderate toxicity encouraged the further design of therapeutically relevant compounds. A new group of selective inhibitors of human immunodeficiency virus integrase (inhibited both 3?-processing and strand transfer reactions catalyzed by IN) – derivatives of 3-(furan-2-yl)spiro[5,5]undecane-1,5,9-trione type.
• 1-Substituted derivatives of dihydrothebainehydroquinone are obtained and the possibility of their use in the synthesis of hybrid structures with different cores present in natural products was established. Several approaches to the selective introduction of indolizine fragment into the anthanylate moiety of lappaconitine and N-desacetyllappaconitine have been developed A method of the chemical modification of the structure of the available sesquiterpene ?-methylidene-?-lactone isoalantolactone by means of palladium-catalyzed reaction with versatile aryl halides is developed.
• Derivatives of eudesmane type ?-methylidene-?-lactones, containing aromatic or heterocyclic substituents in the position C(13) were synthesized.
• New methods for preparation of 3-alkenylfurocoumarins, 3-aryl(hetaryl)furocoumarins by the cross-coupling reaction of oreoselones triflate with various vinyl substituted compounds or boronic acids has been proposed. A series of heterocyclic analogues of combretastatine A-4 containing a furocoumarin-modified A- or B-ring are obtained.

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 researches

• 5.6. Химические проблемы создания фармакологически активных веществ нового поколения.
• V.48. Фундаментальные физико-химические исследования механизмов физиологических процессов и создание на их основе фармакологических веществ и лекарственных форм для лечения и профилактики социально значимых заболеваний.

Grants of 2012 year

• Grant of RFBR No. 11-03-00242-а
  Direct transition metal-catalyzed transformations of isoquinoline alkaloids, labdanoids, sesquiterpenoids and furocoumarins. New lead compounds from plant metabolites.
• Grant of RFBR No. 12-03-00535
  Creation of perspective biologically active molecules for medicinal applications by synthetic modification of accessible plant metabolites.
• Grant of RFBR No. 12-03-92200
  Renewable resources for development and production of new agents for treatment of particularly dangerous diseases. Directed Synthetic Transformations of plant alkaloids, sesquiterpenoids and phenolic compounds from Siberian and Mongolian Flora.
• Grant of RFBR No. 12-03-90838-young_RF_sр
  Investigation and isolation of plant metabolites from plants of Apiaceae family as a target for development of biologically active compounds with tasked properties. Scientific project of Taraskin Vasilii Vladimirovich from Buryat State University in Novosibirsk Institute of Organic Chemistry.
• Grant of RFBR No.12-03-31096 
  Direct transformations of coumarins by Pd- and Cu-catalyzed reactions.
• Interdisciplinary joint project SB RAS and Far-East Branch of RAS No 51.
  Investigation of metabolites from sea and plant origin as a base for design of important medicinal preparations.
• Joint project SB RAS and JSC International research and Production holding “Phytochemistry” No. 108.
  Investigation of chemical modifications of available plant metabolites of Kazakhstan and Siberian flora. Searching of new agents for drugs development
• Joint project SB RAS and Institute of Bioorganic Chemistry of the National Academy of Sciences of Belarus No 23.
  Synthetic transformations of pentacyclic triterpenoids as a convenient way for discovering of perspective pharmacologically useful agents.
• Project of RAS No FSM-44.
  “Direct synthetic transformations of labdane-type diterpenoids for development of new analgesics with selectivity of actions”.
• Project of RAS No 5.9.2.
  “Direct synthetic transformations of low-molecular plant metabolites and their derivatives. New lead-compounds and sources for treatment of particularly dangerous diseases”.

Research papers(Last& Main)

1. Ю.В. Харитонов, Э.Э. Шульц, М.М. Шакиров, И.Ю. Багрянская, Г.А. Толстиков. Синтетические трансформации высших терпеноидов. XXIX. Катализируемая золотом циклоизомеризация пропаргиламинометил- и пропаргилоксиметилзамещенных фуранолабданоидов. Журнал органической химии. 2012. Т. 48. Вып. 8. C. 1085-1092.
2. М.Е. Миронов, Э.Э. Шульц, М.М. Шакиров, Ю.В. Харитонов, Г.А. Толстиков. Синтетические трансформации высших терпеноидов. XXVIII. Диеновый синтез с участием 16-(триметилсилоксибутадиенил)лабданоидов. Журнал органической химии. 2012. Т. 48. Вып. 6. С. 842–852.
3. В.Е. Романов, Э.Э. Шульц, М.М. Шакиров, Г.А. Толстиков. Исследование алкалоидов флоры Сибири и Алтая. XVIII. 2-Ацетамидо-5-[2-(пиридил-3-ил)винил]бензоаты в синтезе индолизинов антранилатного типа. Журнал органической химии. – 2011. Т. 47. Вып. 4. C. 578-585 (p. 581-588).
4. А.В. Липеева, Э.Э. Шульц, М.М. Шакиров, Г.А. Толстиков. Исследование растительных кумаринов. 7. Аминирование трифлата ореозелона. Журнал органической химии. 2011. Т. 47. Вып. 9. C.1367-1379.
5. А.В. Беловодский, Э.Э. Шульц, М.М. Шакиров, И.Ю. Багрянская, Ю.В. Гатилов, Г.А. Толстиков. Синтетические трансформации метиленлактонов эудесманового типа. Поведение изоалантолактона в условиях реакции Хека. Журнал органической химии. 2010. Т. 46. Вып. 11. C. 1710-1724.
6. Э.Э. Шульц, Д.С. Олейников, И.В. Нечепуренко, M.М. Шакиров, Г.А. Толстиков. Синтетические трансформации высших терпеноидов. XVIII. Cинтез оптически активных производных 9,10-антрахинона. ЖОрХ. 2009. Т. 45. Вып. 1. C. 102-114.
7. В.Т. Бауман, Э.Э. Шульц, M.М. Шакиров, Г.А. Толстиков. Синтетические трансформации изохинолиновых алкалоидов. Синтез новых производных дигидротебаингидрохинона. Изв. АН. Сер. хим., 2007, 1206.
8. E.E. Shults, E.A. Semenova, A.A. Johnson, S.P. Bondarenko, I.Y. Bagryanskaya, Y.V. Gatilov , G.A. Tolstikov, Y. Pommier. Synthesis and HIV-1 Integrase Inhibitory Activity of Spiroundecane(ene) Derivatives. Bioorg. Med. Chem. Lett., 2007, 17, 1362.
9. С.А. Осадчий, Э.Э. Шульц, Е.В. Полухина, М.M. Шакиров, Г.А. Толстиков. Исследование алкалоидов флоры Сибири и Алтая. Сообщение 12. Синтез новых производных лаппаконитина, содержащих олефиновые заместители. Известия АН. Серия химическая. 2006. № 6. 1038-1044.
10. E.E. Shults, J. Velder, H.-G. Schmalz, S.V. Chernov, T.V. Rubalova, Y.V. Gatilov, G. Henze, G.A. Tolstikov and A. Prokop. Gram-scale synthesis of pinusolide and evaluation of its antileukemic potential. Bioorg. Med. Chem. Lett., 2006, 16, 4228.