Конструирование и синтез искусственных рибонуклеаз на основе 1,4-диазабицикло(2.2.2) октана и имидазола тема автореферата и диссертации по химии, 02.00.10 ВАК РФ

ОГЛАВЛЕНИЕ.

ВВЕДЕНИЕ.

НЕПРИРОДНЫЕ КАТАЛИЗАТОРЫ ГИДРОЛИЗА РНК.

ТИПИЧНЫЕ СТРУКТУРЫ АКТИВНЫХ ЦЕНТРОВ И МЕХАНИЗМЫ ДЕЙСТВИЯ ПРИРОДНЫХ ФОСФОЭСТЕРОЛИТИЧЕСКИХ

ФЕРМЕНТОВ.

ОБЩИЕ ПРИНЦИПЫ КОНСТРУИРОВАНИЯ ИСКУССТВЕННЫХ

РИБОНУКЛЕАЗ.

Дизайн каталитических доменов.

Виды РНК-связывающих доменов.

ПРИМЕРЫ РЕАЛЬНЫХ КОНСТРУКЦИЙ.

Металлозависимые искусственные рибонуклеазы.

Металлонезависимые искусственные рибонуклеазы.

Искусственные РНКазы, содержащие каталитические центры различной природы.

РЕЗУЛЬТАТЫ И ИХ ОБСУЖДЕНИЕ.

ВЫВОДЫ ИЗ ОБЗОРА ЛИТЕРАТУРЫ И ЗАДАЧИ ДИССЕРТАЦИИ.

ДИЗАЙН ИСКУССТВЕННЫХ РИБОНУКЛЕАЗ ХА"В^кСт.

СИНТЕЗ ИСКУССТВЕННЫХ РИБОНУКЛЕАЗ ХА-В^С"1.

Общая стратегия синтеза.

Конструирование активированных эфиров, содержащих РНКсвязывающий домен.

Сшивка" РНК-связывающего и каталитического центров.

Получение полизарядных искусственных рибонуклеаз ХА"В!ЬкСт.

Дизайн и синтез "усеченных" искусственных рибонуклеаз.

Характеризация синтезированных соединений.

Возможности варьирования доменной структуры, природы доменов и геометрии молекулы в рамках предложенной стратегии синтеза.

ГИДРОЛИЗ РНК ИСКУССТВЕННЫМИ РИБОНУКЛЕАЗАМИ ХАпВ1ЬкСт.

Основные закономерности процесса гидролиза РНК в присутствии синтезированных искусственных рибонуклеаз.

Зависимость гидролитической активности искусственной РНКазы от строения каталитического центра.

Зависимость рибонуклеазной активности конъюгатов от суммарного положительного заряда субстрат-связывающего центра.

Зависимость рибонуклеазной активности конъюгатов от расстояния между каталитическим и РНК-связывающим доменами.

Наличие всех доменов - необходимое условие высокой каталитической активности искусственной РНКазы.

РЕКОМЕНДАЦИИ ДЛЯ ПРОДОЛЖЕНИЯ РАБОТ ПО ФУНКЦИОНАЛЬНОМУ СОВЕРШЕНСТВОВАНИЮ ИСКУССТВЕННЫХ РИБОНУКЛЕАЗ.

ЭКСПЕРИМЕНТАЛЬНАЯ ЧАСТЬ.

ОБЩИЕ ПОЛОЖЕНИЯ.

Материалы.

Общеупотребительные методы.

ОРГАНИЧЕСКИЙ СИНТЕЗ.

БЛАГОДАРНОСТИ.

ВЫВОДЫ.

выводы

1. Сконструированы искусственные рибонуклеазы нового класса, в структурах которых содержатся: имидазолсодержащие функциональные группы, активные в кислотно-основном катализе; бис-четвертизованный 1,4-диазабицикло[2.2.2]октан, РНК- связывающая группировка поликатионной природы; липофильный углеводородный радикал.

2. Разработана простая универсальная стратегия синтеза предложенных конструкций, позволяющая в широких пределах варьировать как доменную структуру молекулы в целом, так и ее отдельные структурные параметры, влияющие на каталитическую активность: строение каталитического домена, число положительных зарядов в субстрат-связывающем домене, взаиморасположение этих доменов путем изменения длины соединяющего их линкера, липофильность конъюгатов путем изменения размера алифатического углеводородного радикала.

Схемой синтеза предусмотрена также возможность введения в состав молекулы дополнительных функциональных групп.

С использованием разработанных синтетических подходов получены и охарактеризованы 37 новых соединений; выбор целевых структур определялся возможностью формирования гомологических рядов, в которых конструкции отличаются друг от друга только одним параметром.

3. Предложенные соединения проявили высокую гидролитическую активность в реакции расщепления РНК и сходную специфичность в отношении нуклеотидных последовательностей. Показано, что для проявления высокой рибонуклеазной

126 активности необходимо наличие в структуре их молекул всех предложенных доменов: имидазолсодержащего каталитического, положительно заряженного РНК-связывающего, а также липофильного радикала. Сравнительный анализ действия синтезированных конструкций внутри гомологических рядов позволил определить оптимальное строение каждого из доменов и их взаимное расположение.

1. DNA and RNA Cleavers and Chemotherapy of Cancer and Viral Diseases // NATO ASI Ser., Ser. C. 1996. V. 479. 372 pp.

2. Raines R.T. Ribonuclease A: from model system to cancer chemotherapeutic // Biomed. Health Res. 1999. V. 27. P. 235-249.

3. Hegg E.L., Burstyn J.N. Toward the development of metal-based synthetic nucleases and peptidases: a rationale and progress report in applying the principles of coordination chemistry// Coord. Chem. Rev. 1998. V. 173. P. 133-165.

4. Kozlowski H., Bal W., Dyba M., Kowalik-Jankowska T. Specific structure-stability relations in metallopeptides// Coord. Chem. Rev. 1999. V. 184. P. 319-346.

5. Kimura E., Dimetallic hydrolases and their models // Curr. Opin. Chem. Biol. 2000. V. 4. P. 207-213.

6. Strater N., Lipscomb W. N., Klabunde T., Krebs B. Two-metal ion catalysis in enzymic acyl- and phosphoryl-transfer reactions // Angew. Chem., Int. Ed. Engl. 1996. V. 35. P. 2025-2055.

7. Wilcox D.E. Binuclear metallohydrolases // Chem. Rev. 1996. V. 96. P. 2435-2458.

8. Cowan J. A. Metal Activation of Enzymes in Nucleic Acid Biochemistry // Chem. Rev. 1998. V. 98. P. 1067-1087.

9. Kovall R.A., Matthews B.W. Type II restriction endonucleases: structural, functional and evolutionary relationships // Curr. Opin. Chem. Biol. 1999. V. 3. P. 578-583.

10. Iwasaki Y., Horiike S., Matsushima K., Yamane T. Location of the catalytic nucleophile of phospholipase D of Streptomyces antibioticus in the C-terminal half domain // Eur. J. Biochem. 1999. V. 264. P. 577-581.

11. Gottlin E.B., Rudolph A.E., Zhao Y., Matthews H.R., Dixon J.E. Catalytic mechanism of the phospholipase D superfamily proceeds via a covalent phosphohistidine intermediate

12. HProc. Natl. Acad. Sci. USA. 1998. V. 95. P. 9202-9207.

13. Holtz K.M., Kantrowitz E.R. The mechanism of the alkaline phosphatase reaction: insights from NMR, cristallography and site-specific mutagenesis // FEBS Lett. 1999. V. 462. P. 7-11.

14. Zhang M., Van Etten R.L., Stauffacher C.Y. Crystal structure of bovine heart phosphotyrosyl phosphatase at 2.2A resolution II Biochemistry. 1994. V. 33. P. 1109711105.

15. Общая органическая химия; Пер. с англ. / Под ред. Д. Бартона и У. Д. Оллиса. М.: Химия, 1983. Т. 4, 728 с.

16. Aqvist J., Kolmodin К., Florian J., Warshel A. Mechanistic alternatives in phosphate monoester hydrolysis: what conclusions can be drawn from available experimental data? // Chem. Biol. 1999. V. 6. P. R71-R80.

17. Gerlt J. A., Gassman P.G. Understanding the rates of certain enzyme-catalyzed reactions: proton abstraction from carbon acids, acyl-transfer reactions, and displacement reactions of phosphodiesters II Biochemistry. 1993. V. 32. P. 11943-11952.

18. Lim C., Tole P. Endocyclic and Exocyclic Cleavage of Phosphorane Monoanion: A Detailed Mechanism of the RNase A Transphosphorylation Step // J. Am. Chem. Soc. 1992. V. 114. P. 7245-7252.

19. Hondal R.J., Zhao Z., Kravchuk A.V., Liao H., Riddle S.R., Yue X., Bruzik K.S., Tsai M.-D. Mechanism of Phosphatidylinositol-Specific Phospholipase С: A Unified View of the Mechanism of Catalysis // Biochemistry. 1998. V. 37. P. 4568-4580.

20. Bashkin J.K., Jenkins L.A. The role of metals in the hydrolytic cleavage of DNA and RNA// Comments Inorg. Chem. 1994. V. 16. P. 77-93.

21. Shindo H., Hayes M.B., Cohen J.S. Nuclear magnetic resonance titration curves of histidine ring protons. A direct assignment of the resonances of the active site histidine residues of ribonuclease // J. Biol. Chem. 1976. Y. 251. P. 2644-2647.

22. Pace C.N., Heinemann U., Hahn U., Saenger W. Ribonuclease Tl: Structure, function, and stability //Angew. Chem. Int. Ed. Engl. 1991. V. 30. P. 343-360.

23. Sowa G.A., Hengge A.C., Cleland W.W. 180 Isotope Effects Support a Concerted Mechanism for Ribonuclease A // J. Am. Chem. Soc. 1997. V. 119. P. 2319-2320.

24. Schultz L.W., Quirk D.J., Raines R.T. His-Asp Catalytic Dyad of Ribonuclease A: Structure and Function of the Wild-Type, D121N, and D121A Enzymes // Biochemistry. 1998. Y. 37. P. 8886-8898.

25. Perreault D.M., Anslyn E.V. Unifying the current data on the mechanism of cleavage-transesterification of RNAII Angew. Chem., Int. Ed. Engl. 1997. V. 36. P. 433-450.

26. Volbeda A., Lahm A., Sakiyama F., Suck D. Crystal structure of Penicillium citrinum PI nuclease at 2.8 A resolution // EMBO J. 1991. V. 10. P. 1607-1618.

27. Romier C., Dominguez R., Lahm A., Dahl O., Suck D. Recognition of single-stranded DNA by nuclease PI: high resolution crystal structures of complexes with substrate analogs II Proteins: Struct., Funct, Genet. 1998. V. 32. P. 414-424.

28. Knofel T., Strater N. X-ray structure of the Escherichia coli periplasmic 5'-nucleotidase containing a dimetal catalytic site // Nat. Struct. Biol. 1999. V. 6. P. 448-453.

29. Klabunde T., Krebs B. The dimetal center in purple acid phosphatases // Struct. Bonding. 1997. V. 89. P. 177-198.

30. Weber D.J., Meeker A.K., Mildvan A.S. Interactions of the acid and base catalysis on

31. Staphilococcl nuclease as studied in a double mutant // Biochemistry. 1991. V. 30. P. 61036114.

32. Pratviel G., Bernadou J., Meunier В. DNA and RNA cleavage by metal complexes // Adv. Inorg. Chem. 1998. V. 45. P. 251-312.

33. Thorp H.H. The importance of being r: greater oxidative stability of RNA compared with DNA // Chem. Biol. 2000. V 7. P. R33-R36.

34. Tuschl Т., Thomson J.B., Eckstein F. RNA cleavage by small catalytic RNAs // Curr. Opin. Struct. Biol. 1995. V. 5. P. 296-302.

35. Jaeger L. The new world of ribozymes // Curr. Opin. Struct. Biol. 1997. V. 7. P. 324335.

36. Walter N.G., Bruke J.M. The hairpin ribozyme: structure, assembly and catalysis // Curr. Opin. Chem. Biol. 1998. V. 2. P. 24-30.

37. Scott W.G. RNA catalysis // Curr. Opin. Struct. Biol. 1998. V. 8. P. 720-726.

38. SenD., Geyer C.R. DNA enzymes // Curr. Opin. Chem. Biol. 1998. V. 2. P. 680-687.

39. Serpersu E.H., McCracken J., Peisach J., Mildvan A.S. Electron spin echo modulation and nuclear relaxation studies of staphylococcal nuclease and its metal-coordinating mutants // Biochemistry. 1988. V. 27. P. 8034-8044.

40. Menger F.M., Whitesell L.G. A protease Mimic with Turnover Capabilities // J. Am. Chem. Soc. 1985. V. 107. P. 707.

41. Menger F.M., Percichetti R.A. Two New Amphiphilic Catalysts for Esters Hydrolysis //

42. J. Org. Chem. 1987. V. 52. P. 3451-3452.

43. Yashiro M., Ishikubo A., Komiyama M. Preparation and study of dinuclear zinc(II) complex for the efficient hydrolysis of the phosphodiester linkage in a diribonucleotide // J. Chem. Soc., Chem. Commun. 1995. V. 17. P. 1793-1794.

44. Morrow J.R., Kolasa K.A., Amin S., Chin K.O.A. Metal ion macrocyclic complexes as artificial ribonucleases II Adv. Chem. Ser. 1995. V. 246. P. 431-447.

45. Putnam W.C., Bashkin J.K. De novo synthesis of artificial ribonucleases with benign metal catalysts // Chem. Commun. (Cambridge). 2000. V. 9. P. 767-768.

46. Liu S., Hamilton A.D. Catalysis of phosphodiester transesterification by Cu(II)-terpyridine complexes with peripheral pendent base groups: implications for the mechanism// Tetrahedron Lett. 1997. V. 38. P. 1107-1110.

47. Mukherjee R.N. A dicopper (II) complex hydrolyzes the phosphate diester bond! // Resonance. 1996. V. 1. P. 58-60.

48. Jenkins A.L.A., Bashkin J.K. Transesterification of RNA by Cu(II) terpyridine // Inorg. Chim. Acta. 1997. V. 263. P. 49-52.

49. Liu S., Luo Z., Hamilton A.D. Rapid and highly selective cleavage of ribonucleoside 2',3'-cyclic monophosphates by dinuclear Cu(II) complexes // Angew. Chem., Int. Ed. Engl. 1997. V. 36. P. 2678-2680.

50. Hall K.B., Fox R.O. Directed Cleavage of RNA with Protein-Tethered EDTA-Fe II Methods. 1999. V. 18. P. 78-84.

51. Komiyama M., Sumaoka J., Yonezawa K., Matsumoto Y., Yashiro M. Structurereactivity relationship for the cobalt(III) complex-catalyzed hydrolysis of adenosine 3',5'-cyclic monophosphate II J. Chem. Soc., Perkin Trans. 2. 1997. V. 1. P. 75-78.

52. Komiyama M., Matsumoto Y., Takahashi H., Shiiba T., Tsuzuki H., Yajima H., Yashiro M., Sumaoka J. RNA hydrolysis by cobalt(III) complexes // J. Chem. Soc., Perkin Trans. 2. 1998. Y. 3. P. 691-695.53

53. Sumaoka J., Uchida H., Komiyama M. Acetylacetonato-lanthanide complexes as eminent catalytic sites for artificial ribonucleases // Nucleic Acids Symp. Ser. 1995. V. 34. P. 83-84.

54. Haner R., Hall J., Rihs G. Synthesis and structure of a macrocyclic europium complex and its possible role as a catalyst for phosphodiester transesterification // Helv. Chim. Acta. 1997. V. 80. P. 487-494.

55. Baker B.F., Khalili H., Wei N., Morrow J.R. Cleavage of the 5'-Cap Structure of mRNA by a Europium(III) Macrocyclic Complex with Pendant Alcohol Groups // J. Am. Chem. Soc. 1997. V. 119. P. 8749-8755.

56. Miyama S., Asanuma H., Komiyama M. Hydrolysis of phosphomonoesters in nucleotides by cerium(IV) ions. Highly selective hydrolysis of monoester over diester in concentrated buffers II J. Chem. Soc. Perkin Trans. 2. 1997. V. 9. P. 1685-1688.

57. Bracken K., Moss R.A., Ragunathan K.G. Remarkably Rapid Cleavage of a Model Phosphodiester by Complexed Ceric Ions in Aqueous Micellar Solutions // J. Am. Chem. Soc. 1997. V. 119. P. 9323-9324.

58. Wang C., Choudhary S., Vink C.B., Secord E.A., Morrow J.R. Harnessing thorium(IV) as a catalyst: RNA and phosphate diester cleavage by a thorium(IV) macrocyclic complex // Chem. Commun. (Cambridge). 2000. V. 24. P. 2509-2510.

59. Pratviel G., Bernadou J., Meunier B. Selective DNA cleavage by metalloporphyrin derivatives II Met. Ions Biol. Syst. 1996. V. 33. P. 399-426.

60. Напег R., Husken D., Hall J. Development of artificial ribonucleases using macrocyclic lanthanide complexes // Chimia. 2000. V. 54. P. 569-573.

61. Kazakov S.A. Nucleic Acid Binding and Catalysis by Metal Ions // Bioorganic Chemistry: Ed. S.M. Hecht, New York: Oxford University Press, 1996. P. 224.

62. Behlen L.S., Sampson J.R., DiRenzo A.B., Uhlenbeck O.C. Lead-catalyzed cleavage of yeast tRNAphe mutants II Biochemistry. 1990. V. 29. P. 2515-2523.

63. Wrzesinski J., Michalowski D., Ciesiolka J., Krzyzosiak W.J. Specific RNA cleavages induced by manganese ions И FEBSLett. 1995. V. 374. P. 62-68.

64. Kolchanov N.A., Titov I.I., Vlassova I.E., Vlassov V.V. Chemical and computer probing of RNA structure // Prog. Nucl. Acids Res. Mol. Biol. 1996. V. 53.P. 131-196.

65. Ciesiolka J., Yarns M. Small RNA-divalent domains // RNA. 1996. V. 2. P. 785-793.

66. Majerfeld I., Yarns M. Isoleucine:RNA sites with associated coding sequences // RNA. 1998. V. 4. P. 471-478.

67. Baykal U., Akkaya E.U. Synthesis and phosphodiester transesterification activity of thei I1. -complex of a novel functionalized octadentate ligand // Tetrahedron Lett. 1998. V. 39. P. 5861-5864.

68. Breslow R., Berger D., Huang D. Bifunctional zinc-imidazole and zinc-thiophenol catalysts// J. Am. Chem. Soc. 1990. V. 112.P. 3686-3687.

69. Г.К. Боресков. Гетерогенный катализ. -M: Наука, 1986. гл. 2. С. 18-37.

70. Chung Y., Akkaya E.U., Venkatachalam Т.К., Czarnik A.W. Synthesis and characterization of reactive binuclear Co(III) complex. Cooperative promotion of phosphodiester hydrolysis// Tetrahedron. 1990. V. 31. P. 5413-5416.

71. Сильников B.H., Лукьянчук Н.П., Шишкин Г.В., Жиже Р., Власов В.В. Имидазолсодержащие производные, моделирующие активный центр РНКазы А. Синтез и РНК-расщепляющая активность И Докл. АН. 1999. Т. 364. С. 690-694.

72. Luedtke N.W., Baker Т. J., Goodman М., Tor Y. Guanidinoglycosides: a novel family of RNA ligands И J. Am. Chem. Soc. 2000. Y. 122. P. 12035-12036.

73. Breslow R. Biomimetic reactions directed by templates and removable tethers // Templated Org. Synth: Ed. F. Diederich and P. J. Stang. Weinheim: Wiley-VCH Yerlag GmbH, 2000. P. 159-188.

74. Atassi M. Z. Preparation of cyclic peptide catalysts modeled on enzyme active sites // US Pat. 5861477; Chem. Abstrs. 1999. V. 130: 110645.

75. Kalesse M., Oost T. RNAse active site model systems // Bioorg. Chem: Ed. U. Diederichsen, Weinheim: Wiley-VCH Verlag GmbH, 1999. P. 272-280.

76. Breslow R., Dong S.D. Biomimetic Reactions Catalyzed by Cyclodextrins and Their Derivatives // Chem. Rev. 1998. V. 98. P. 1997-2011.

77. Haner R., Hall J. The sequence-specific cleavage of RNA by artificial chemical ribonucleases // Antisense Nucleic Acid Drug Dev. 1997. V. 7. P. 423-430.

78. Haener R., Hall J., Pfuetzer A., Huesken D. Development of artificial ribonucleases // Pure Appl. Chem. 1998. V. 70. P. 111-116.

79. Matsuda S., Yashiro M., Komiyama M. Design and synthesis of novel artificial ribonucleases containing zinc(II) complexes: site-selective RNA hydrolysis by thecooperation of two zinc(II) ions // Nucleic Acids Symp. Ser. 1998. V. 39. P. 225-226.

80. Matsuda S., Ishikubo A., Kuzuya A., Yashiro M., Komiyama M. Conjugates of a dinuclear zinc(II) complex and DNA oligomers as novel sequence-selective artificial ribonucleases // Angew. Chem., Int. Ed. 1998. V. 37. P. 3284-3286.

81. Inoue H., Shimizu M., Furukawa T., Tamura T., Matsui M., Ohtsuka E. Site-specific RNA cleavage using terpyridine+Cu(II)-linked 2'-0-methyloligonucleotides II Nucleosides Nucleotides. 1999. V. 18. P. 1503-1505.

82. Tamura T., Furukawa T., Komatsu Y., Ohtsuka E., Inoue H. Toward artificial ribonucleases: design and synthesis of 2'-0-methyloligonucleotides with a terpyridine-copper(II) complex // Nucleic Acids Symp. Ser. 1999. V. 42. P. 109-110.

83. Duarte V., Sixou S., Favre G., Pratviel G., Meunier B. Oxidative damage on RNA mediated by cationic metalloporphyrin-antisense oligonucleotides conjugates // J. Chem. Soc., Dalton Trans. 1997. V. 21. P. 4113-4118.

84. Haener R., Hall J., Huesken D., Pieles U., Moser H. Preparation of terpyridine metal complexes and their oligonucleotide conjugates as RNA cleavage reagents // US Pat. 5925744; Chem. Abstrs. 1996. V. 125:115078.

85. Adams T.H., Reynolds M.A. Antisense oligonucleotide complexes with metal ascleavage-enhancing agents to inhibit mRNA translation and use for disease therapy // PCT Int. Appl. WO 9606621; Chem. Abstrs. 1996. V. 125:1348.

86. Haner R., Hall J., Husken D., Moser H.E. Sequence-specific cleavage of RNA using lanthanide complexes linked to oligonucleotides // NATO ASI Ser., Ser. C. 1996. V. 479. P. 307-320.

87. Huang L., Chappell L.L., Iranzo O., Baker B.F., Morrow J.R. Oligonucleotide conjugates of Eu(III) tetraazamacrocycles with pendent alcohol and amide groups promote sequence-specific RNA cleavage II J. Biol. Inorg. Chem. 2000. V. 5. P. 85-92.

88. Kuzuya A., Akai M., Komiyama M. Non-covalent combinations of lanthanide(III) ion and two DNA oligomers for sequence-selective RNA scission // Chem. Lett. 1999. V. 10. P. 1035-1036.

89. Kuzuya A., Komiyama M. Non-covalent ternary systems (DNA-acridine hybrid/DNA/lanthanide(iii)) for efficient and site-selective RNA scission // Chem. Commun. (Cambridge). 2000. V. 20. P. 2019-2020.

90. Kuzuya A., Komiyama M. Sequence-selective RNA scission by non-covalent combination of acridine-tethered DNA and lanthanide(HI) ion // Chem. Lett. 2000. V. 12. P. 1378-1379.

91. Komiyama M. Sequence-specific and hydrolytic scission of DNA and RNA by lanthanide complex-oligoDNA hybrids // / Biochem. 1995. V. 118. P. 665-670.07

92. Trawick B.N., Daniher A.T., Bashkin J.K. Inorganic Mimics of Ribonucleases and Ribozymes: From Random Cleavage to Sequence-Specific Chemistry to Catalytic

93. Antisense Drugs // Chem. Rev. 1998. V. 98. P. 939-960.1. OR

94. Власов В.В., Сильников В.Н., Зенкова М.А. Химические Рибонуклеазы П Мол. биология. 1998. Т. 32. С. 62-69.

95. Komiyama М., Sumaoka J. Progress towards synthetic enzymes for phosphoester hydrolysis // Curr. Opin. Chem. Biol. 1998. Y. 2. P. 751-757.

96. Сильников B.H., Власов B.B. Конструирование реагентов для направленного расщепления рибонуклеиновых кислот // Успехи хим. 2001. Т. 70. С. 562-580.

97. Costamagna J., Feraudi G., Matsuhiro В., Campos-Vallette M., Canales J., Villagran M., Vargas J., Aguirre M.J. Complexes of macrocycles with pendant arms as models for biological molecules // Coord. Chem. Rev. 2000. V. 196. P. 125-164.

98. Yamada K., Takahashi Y., Yamamura H., Araki S., Kawai M., Saito K. Phosphodiester bond cleavage mediated by a cyclic p-sheet peptide-based dinuclear zinc(II) complex // Chem. Commun. (Cambridge). 2000. V. 14. P. 1315-1316.

99. Michaelis K., Kalesse M. Selective cleavage of the HIV-l TAR-RNA with peptide-cyclen conjugate // Angew. Chem. Int. Ed. 1999. V. 38. P. 2243-2245.

100. Dong S.D., Breslow R. Bifunctional cyclodextrin metalloenzyme mimics // Tetrahedron Lett. 1998. V. 39. P. 9343-9346.

101. Vlassov V.V., Zuber G., Felden В., Behr J.-P., Giege R. Cleavage of tRNA with imidazole and spermine imidazole constructs: a new approach for probing RNA structure // Nucl. Acids Res. 1995. V. 23. P. 3161-3167.

102. Endo M., Hirata К., Шага Т., Sueda S., Takagi M., Komiyama M. RNA Hydrolysis by the Cooperation of Carboxylate Ion and Ammonium Ion II J. Am. Chem. Soc. 1996. V. 118. P. 5478-5479.

103. Lorente A., Espinosa J.F., Fernandez-Saiz M., Lehn J.-M., Wilson W.D., Zhong Y.Y. Syntheses of imidazole-acridine conjugates as ribonuclease A mimics II Tetrahedron Lett.1996. V. 37. P. 4417-4420.

104. Kato T., Takeuchi T., Karube I. Bis-imidazolyl cleft-shaped mimic of the active site of ribonuclease A // Chem. Commun. 1996. V. 8. P. 953-954.

105. Podyminogin M.A., Vlassov V.Y., Giege R. Synthetic RNA-cleaving molecules mimicking ribonuclease A active center. Design and cleavage of tRNA transcripts // Nucl. Acids Res. 1993. V. 21. P. 5950-5956.

106. Kurz K., Goebel M.W. Hydrolytical cleavage of TAR-RNA, the trans-activation responsive region of HIV-1, by a bis(guanidinium) catalyst attached to arginine // Helv. Chim. Acta. 1996. V. 79. P. 1967-1979.

107. Oost T., Kalesse M. Synthesis of RNase active site model systems using steroid template// Tetrahedron. 1997. V. 53. P. 8421-8438.

108. Oost T., Filipazzi A., Kalesse M. Bis(guanidinium) receptors as ribonuclease active-site model systems. Structural changes and solvent effects // Liebigs Ann./Recl. 1997. V. 5. P. 1005-1011.

109. Shinozuka K., Shimizu K., Nakashima Y., Sawai H. Synthesis ans RNA cleaving activities of polyamine derived novel artificial ribonuclease // Bioorg. Med. Chem. Lett. 1994. V. 4. P. 1979.

110. Prakash T.P., Kunta S.S., Ganesh K.N. Self cleavage of C8-Histamino-r(UpA) Promoted by ZnC^: Mechanistic Studies on Designed Ribonuclease Mimic // Tetrahedron. 1994. V. 50. P. 11699-11708.

111. Komiyama M., Yoshinari K. Kinetic Analysis of Diamine-Catalyzed RNA Hydrolysis // J. Org. Chem. 1997. V. 62. P. 2155-2160.

112. Bibillo A., Figlerowicz M., Kierzek R. The non-enzymatic hydrolysis of oligoribonucleotides VI. The role of biogenic polyamines // Nucleic Acids Res. 1999. V. 27. P. 3931-3937.

113. Li X.H., Wan R., Zhang Q., Zhao Y.F. The cleavage effect of histidyl-lysine on RNA // Chin. Chem. Lett. 1998. V. 9. P. 333-334.

114. Perello М., Barbier В., Brack A. Hydrolysis of oligoribonucleotides by alpha-helical basic peptides II Int. J. Protein Res. 1991. V. 38. P. 154-160.

115. Barbier В., Brack A. Conformation-controlled hydrolysis of polyribonucleotides by equential basic polypeptides // J. Am. Chem. Soc. 1992. V. 114. P. 3511-3515.

116. Ma Y., Zhao Y. Different function of cysteine and Serine residue on RNA and DNA // Phosphorus, Sulfur and Silicon. 1997. V. 120. P. 447-448.

117. Silnikov V., Zuber G., Behr J.-P., Giege R., Ylassov Y. Design of ribonuclease mimics for sequence specific cleavage of RNA II Phosphorus, Sulfur Silicon Relat. Elem. 1996. V. 109-110. P. 277-280.

118. Shinozuka K., Nakashima Y., Shimizu K., Sawai H. Synthesis and characterization of polyamine-based biomimetic catalysts as artificial ribonuclease II Nucleosides, Nucleotides Nucleic Acids. 2001. V. 20. P. 117-130.

119. Zhdan N.S., Kuznetsova I.L., Zenkova M.A., Vlassov A.V., Silnikov V.N., Giege R., Vlassov V.V. Synthesis and characterization of artificial ribonucleases // Nucleosides Nucleotides. 1999. V. 18. P. 1491-1492.

120. Yan J.-M., Xie R.-G., Zhao H.-M., Wu D.-X., Xia P.-F. Synthesis of dimeric estradiol enzyme model containing imidazolyl and study on its catalytic efficiency in hydrolysis of carboxylates and phosphates // Chin. J. Chem. 1997. Y. 15. P. 438-442.

121. Breslow R., Schmuck C. Goodness of Fit in Complexes between Substrates and Ribonuclease Mimics: Effects on Binding, Catalytic Rate Constants, and Regiochemistry // J. Am. Chem. Soc. 1996. V. 118. P. 6601-6605.

122. Lorthioir O., Truffert J.C., Sy D., Barbier В., Lelievre D., Brack A. Computer design, synthesis and hydrolytic activity of peptidic artificial ribonucleases // Protein Pept. Lett. 1996. V.3.P. 153-160.

123. Vlassov V., Abramova Т., Godovikova Т., Giege R., Silnikov V. Sequence-specific cleavage of yeast tRNAPhe with oligonucleotides conjugated to a diimidazole construct // Antisense Nucleic Acid Drug Dev. 1997. Y. 7. P. 39-42.

124. Pyshnyi D., Repkova М., Lokhov S., Ivanova E., Yenyaminova A., Zarytova V. Oligonucleotide-peptide conjugates for RNA cleavage// Nucleosides Nucleotides. 1997. V. 16. P.1571-1574.

125. Beloglazova N.G., Sil'nikov V.N., Zenkova M.A., Vlassov V.V. Cleavage of yeast tRNAPhe with complementary oligonucleotide conjugated to a small ribonuclease mimic // FEBSLett. 2000. V. 481. P. 277-280.

126. Arnold L.J., Reynolds M.A., Schwartz D.A., Daily W.J. Oligonucleosides for cleavage of target nucleic acids and their use for inhibition of protein production // US Pat. 5854410; Chem. Abstrs. 1996. 124:78684.

127. Shinozuka K., Umeda A., Ozaki H., Sawai H. Synthesis and RNA cleaving activity of oligonucleotides containing novel C-5 substituted 2-deoxyuridine bearing polyamine // Nucleic Acids Symp. Ser. 1996. V. 35. P. 121-122.

128. Endo M., Azuma Y., Komiyama M. Site-selective RNA hydrolysis by a novel artificial ribonuclease: interposition of oligoamine between two DNA oligomers // Nucleic Acids Symp. Ser. 1996. V. 35. P. 81-82.

129. Kuzuya A., Azuma Y., Inokawa T., Yoshinari K., Komiyama M. Sequence-selective RNA scission by oligoamine-DNA conjugates // Nucleic Acids Symp. Ser. 1997. V. 37. P. 209-210.

130. Endo M., Azuma Y., Saga Y., Kuzuya A., Kawai G., Komiyama M. Molecular Design for a Pinpoint RNA Scission. Interposition of Oligoamines between Two DNA Oligomers II J. Org. Chem. 1997. V. 62. P. 846-852.

131. Komiyama M. Artificial ribonuclease comprised of oligoamine-DNA conjugates for sequence-selective RNA scission//Japan Pat. 10191970; Chem. Abstrs. 1998. 129:199805.

132. Shinozuka K., Aoki T., Sawai H. Synthesis and RNA cleaving activity of novel artificial RNase bearing polyamine conjugated a-uridine derivative // Nucleic Acids Symp. Ser. 1998. V. 39. P. 229-230.

133. Molenveld P., Engbersen J.F.J., Reinhoudt D.N. Synthesis of a dinuclear Zn(II)-calix4.arene enzyme model with additional general base groups. Catalytic activity in phosphate diester transesterification // Eur. J. Org. Chem. 1999. P. 3269-3275.

134. Koevari E., Kraemer R. Rapid Phosphodiester Hydrolysis by an Ammonium-Functionalized Copper(II) Complex. A Model for the Cooperativity of Metal Ions and NH-Acidic Groups in Phosphoryl Transfer Enzymes // J. Am. Chem. Soc. 1996. V. 118. P. 12704-12709.

135. Husken D., Goodall G., Blommers M.J .J., Jahnke W., Hall J., Haener R., Moser H.E. Creating RNA bulges: cleavage of RNA in RNA/DNA duplexes by metal ion catalysis // Biochemistry. 1996. V. 35. P. 16591-16600.

136. Tabushi I., Kobuke Y., Imuta J. Molecular recognition of nucleotides by means of ionic interaction in hydrophobic media // Nucl Acids Symp Ser. 1979. V. 6. P. 175-178.

137. Riepe A., Beier H., Gross H. J. Enhancement of RNA self-cleavage by micellar catalysis // FEBSLett. 1999. V. 457. P. 193-199.

138. Russell D.W. Acylation with Esters of p-nitrophenol II Biochem. J. 1961. V. 78. P. 696.

139. Fling M., Minard F.N., Fox S.W. Propyl and Phthaloyl Derivatives of Enantiomorphs of Valine and Leucine II J. Am. Chem. Soc. 1947. V. 69. P. 2466-2467.

140. Fox S.W., Polak E.H., Bullock M.W., Kobayashi Y. Preparation of an Intermediate for Synthesis of Lysine: s-Bromocaproic Acid II J. Am. Chem. Soc. 1951. V. 73. P. 4979-4980.

141. Normant H., Voreux G. Preparation and properties of oo-halogenated valeronitriles // Compt. Rend. 1950. V. 231. P. 703-704.

142. West H. Amidelike coupled derivatives of 6-aminocaproic acid // Faserforsch. u. Textiltech. 1954. V. 5. P. 145-155; Chem. Abstrs. 1955. 49:8117a.

143. Lindlar H. A new catalyst for selective hydrogénation II Helv. Chim. Acta. 1952. V. 35. P. 450.

144. Corey E.J., Nicholaou K.C., Balanson R.D., Machida Y. Useful method for the conversion of azides to amines // Synthesis. 1975. P. 590.

145. The Sadtler Standard Spectra: Nuclear Magnetic Resonance Spectra. Philadelphia, Sadtler Research Laboratory. 1-86, N 1M-48000M (1966-1988).

146. X. Гюнтер. Введение в курс спектроскопии ЯМР: Пер. с англ. М.: Мир, 1984. 480 с.

147. JI. Беллами. Инфракрасные спектры сложных молекул: Пер. с англ. М: ИИЛ, 1963. 590 с.

148. Zenkova M., Beloglazova N., Sil'nikov Y., Ylassov V., Giege R. RNA cleavage by 1,4-diazabicyclo2.2.2.octane-imidazpole conjugates // Methods Enzymol. 2001. V. 341. P. 468-490.

149. Зенкова M.A., Чумакова H.Jl., Власов А.В., Комарова Н.И., Веньяминова А.Г., Власов В.В., Сильников В.Н. Синтетические конструкции функционально имитирующие рибонуклеазу А II Мол. биология. 2000. Т. 34. С. 390-394.

150. Hosaka H., Sakabe I., Sakamoto К., Yokoyama S., Takaku H. Sequence-specific cleavage of oligoribonucleotide capable of forming a stem and loop structure // J. Biol. Chem. 1994. V. 269. P. 20090-20094.

151. Полюдек-Фабини P., Бецрих Т. Органический анализ: Пер. с нем. Л.: Химия, 1981. С. 301.

152. Rudinger J., Florentz C., Giege R. Histidylation by yeast HisRS of tRNA or tRNA-likestructure relies on residues -1 and 73 but is dependent on the RNA context // Nucl. Acids

153. Res. 1994. V. 22. P. 5031-5037. 1

154. Dodonov A.F., Chernushevich I.V., Laiko V.V. Electrospray Ionization on a Reflecting Time-of Flight Mass Spectrometer // Time-of Flight Mass Spectrometry: Ed. R.J.Cotter. ACSSymp. Ser. 1994. V. 549. P. 108-123.

155. Shames S.L., Byers L.D. Acyl substituent Effect on Rates of Acyl Transfer to Thioate, Hydroxide, and Oxy Dianions II J. Am. Chem. Soc. 1981. V. 103. P. 6170-6177.

156. Wunderlin R., Minakakis P., Tun-Kui A., Sharma S.D., Schwyzer R. Melanotropin receptors. I. Synthesis and biological activity of №-(5-bromovaleryl)-Na-deacetyl-a-melanotropin II Helv. Chim. Acta. 1985. V. 68. P. 1-11.

157. Zahn H., Schade F. Nitrophenyl esters II Chem. Ber. 1963. V. 96. P. 1747-1750.