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Structural Properties of Purine and Pyrimidine Analogs

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Molecular and Quantum Pharmacology

Part of the book series: The Jerusalem Symposia on Quantum Chemistry and Biochemistry ((JSQC,volume 7))

Abstract

During the past thirty years, many analogs of naturally occurring purines and pyrimidines have been synthesized and tested for various biological effects [1–6]. A number of these compounds are effective metabolic inhibitors which are useful chemotherapeutically, and others have been valuable as mutagenic agents. In an effort to characterize the specific structural and biological properties of purine and pyrimidine analogs, many laboratories have been engaged in crystallographic investigations of these compounds. These studies have been directed specifically toward evaluating the effects exerted by various substituents on bond lengths and angles, preferred tautomer forms, conformations, hydrogen-bonding properties, and base-stacking interactions. In this paper we shall discuss some of these structural results. Rather than attempt a comprehensive review of purine and pyrimidine analogs, we shall examine four specific types of analogs that have been of special interest in our laboratory (Figure 1). The first type (Figure 1a) includes 5-halogenated uracil derivatives, in which a hydrogen atom of uracil or the methyl group of thymine is replaced by a halogen atom. The second type includes those analogs in which an oxygen atom of a natural base has been replaced by a sulfur atom (Figure 1b). The third type (Figure 1c), is composed of N6-monosubstituted adenine derivatives, and related 6-thiopurine derivatives. The fourth type includes purine nucleosides that possess bulky substituents at the 8-position (Figure 1d). Though these types of compounds represent only a fraction of the analogs that have been investigated, they encompass some striking examples of the mechanisms by which alterations of natural bases can cause subtle structural effects, that, in turn, may affect biological properties.

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References

  1. Brockman, R. W. and Anderson, E. P.: Ann. Rev. Biochem. 32, 463 (1963).

    Article  CAS  Google Scholar 

  2. Brockman, R. W. and Anderson, E. P.: Metabolic Inhibitors, Vol. I, Academic Press, Inc., New York, 1963, pp. 239 - 285.

    Google Scholar 

  3. Hitchings, G. H. and Elion, G. B.: Metabolic Inhibitors, Vol. I, Academic Press, New York 1963, pp. 215 - 237.

    Google Scholar 

  4. Balis, M. E.: Antagonists and Nucleic Acids, North-Holland Publishing Company, Amsterdam 1968.

    Google Scholar 

  5. Roy-Burman, P.: Analogues of Nucleic Acid Components, Springer-Verlag, New York 1970.

    Google Scholar 

  6. Hall, R. H.: The Modified Nucleosides in Nucleic Acids. Columbia University Press, New York 1971.

    Google Scholar 

  7. Kaiser, 1.1.: Biochemistry 10, 1540 (1971).

    Article  Google Scholar 

  8. Rosen, B., Rothman, F., and Weigert, M. G.: J. Mol. Biol. 44, 363 (1969).

    Article  CAS  Google Scholar 

  9. Chaudhuri, N. K., Montag, B. J., and Heidelberger, C.: Cancer Research 18, 318 (1958).

    CAS  Google Scholar 

  10. Horowitz, J. and Chargaff, E.: Nature 184, 1213 (1959).

    Article  CAS  Google Scholar 

  11. Gordon, M. P. and Staehelin, M.: Biochim. Biophys. Acta 36, 351 (1959).

    Article  CAS  Google Scholar 

  12. Baliga, B. S., Hendler, S., and Srinivasan, P. R.: Biochim. Biophys. Acta 186, 25 (1969).

    CAS  Google Scholar 

  13. Dunn, D. B. and Smith, J. D.: Biochem. J. 67, 494 (1957).

    CAS  Google Scholar 

  14. Handschumacher, R. E. and Welch, A. D.: The Nucleic Acids, Vol. Ill, Academic Press, Inc., New York 1960, p. 453.

    Google Scholar 

  15. Watson, J. D. and Crick, F. H. C.: Nature 171, 737 (1953).

    Article  CAS  Google Scholar 

  16. Litman, R. M. and Pardee, A. B.: Biochim. Biophys. Acta 42, 131 (1960).

    Article  CAS  Google Scholar 

  17. Rudner, R.: Biochem. Biophys. Res. Commun. 3, 275 (1960).

    Article  CAS  Google Scholar 

  18. Benzer, S. and Freese, E.: Proc. Nat. Acad. Sci. 44, 112 (1958).

    Article  CAS  Google Scholar 

  19. Champe, S. P. and Benzer, S.: Proc. Nat. Acad. Sci. 48, 532 (1962).

    Article  CAS  Google Scholar 

  20. Freese, E.,: J. Mol. Biol 1, 87 (1959).

    Article  CAS  Google Scholar 

  21. Freese, E.: Brookhaven Symp. Biol 12, 63 (1959).

    Google Scholar 

  22. Lawley, P. D. and Brookes, P.: J. Mol Biol 4, 216 (1962).

    Article  CAS  Google Scholar 

  23. Katritzky, A. R. and Waring, A. J.: J. Chem. Soc., 1540 (1962).

    Google Scholar 

  24. Berens, K. and Shugar, D.: Acta Biochim. Polon. 10, 25 (1963).

    CAS  Google Scholar 

  25. Sobell, H. M.: The Purines: Theory and Experiment, Jerusalem Academic Press, Jerusalem 1972, Israel, pp. 124-146.

    Google Scholar 

  26. Grunberg-Manago, M. and Michelson, A. M.: Biochim. Biophys. Acta 80, 431 (1964).

    CAS  Google Scholar 

  27. Grunberg-Manago, M. and Michelson, A. M.: Biochim. Biophys. Acta 87, 593 (1964).

    CAS  Google Scholar 

  28. Trautner, T. A., Swartz, M. N. and Kornberg, A.: Proc. Natl Acad. Sci. U.S. 48, 449 (1962).

    Article  CAS  Google Scholar 

  29. Ts’o, P. O. P. and Chan, S. I.: J. Am. Chem. Soc. 86, 4176 (1964).

    Article  Google Scholar 

  30. Farquhar, E. L., Downing, M., and Gill, S. J.: Biochem. 1, 1224 (1968).

    Google Scholar 

  31. Nakano, N. I. and Igarashi, S. J.: Biochem. 9, 577 (1970).

    Article  CAS  Google Scholar 

  32. Howard, F. B., Frazier, J., and Miles, H. T.: J. Biol Chem. 244, 1291 (1969).

    CAS  Google Scholar 

  33. Riley, M., and Paul, A. V.: J. Mol. Biol 50, 439 (1970).

    Article  CAS  Google Scholar 

  34. Inman, R. B. and Baldwin, R. L.: J. Mol Biol 5, 172 (1962).

    Article  CAS  Google Scholar 

  35. Riley, M. and Paul, A.: Biochem. 10, 3819 (1971).

    Article  CAS  Google Scholar 

  36. Szer, W. and Shugar, D.: Acta Biochim. Polon. 10, 219 (1963).

    CAS  Google Scholar 

  37. Massoulie, J., Michelson, A. M., and Pochon, F.: Biochim. Biophys. Acta 114, 16 (1966).

    CAS  Google Scholar 

  38. Michelson, A. M. and Monny, C.: Biochim. Biophys. Acta 149, 107 (1967).

    Google Scholar 

  39. Kit, S. and Hsu, T. C.: Biochem. Biophys. Res. Commun. 5, 120 (1961).

    Article  CAS  Google Scholar 

  40. Eaton, M. A. W. and Hutchinson, D. W.: Biochem. 11, 3162 (1972).

    Article  CAS  Google Scholar 

  41. Inman, R. B. and Baldwin, R. L.: J. Mol Biol 8, 452 (1964).

    Article  CAS  Google Scholar 

  42. Radding, C. M., Josse, J., and Kornberg, A.: J. Biol Chem. 237, 2869 (1962).

    CAS  Google Scholar 

  43. Ross, P. D., Scruggs, R. L., Howard, F. B., and Miles, H. T.: J. Mol Biol 61, 727 (1971).

    Article  CAS  Google Scholar 

  44. Chamberlin, M., Baldwin, R. L., and Berg, P.: J. Mol Biol 7, 334, (1963).

    Article  CAS  Google Scholar 

  45. Baldwin, R. L., Inman, R. B., and Wake, R. G.: Federation Proc. 20, 354 (1961).

    Google Scholar 

  46. Davis, K. M. C. and Farmer, M. F.: J. Chem. Soc. (B), 28 (1967).

    Google Scholar 

  47. Schneider, W. G.: J. Phys. Chem 66, 2653 (1962).

    Article  CAS  Google Scholar 

  48. Homer, J. and Cooke, M. C.: J. Chem. Soc. (A), 111 (1969).

    Google Scholar 

  49. Anderson, R. and Prausnitz, J. M.: J. Chem. Phys. 39, 1225, (1963).

    Article  CAS  Google Scholar 

  50. Aroney, M. J., Calderbank, K. E., Le Fevre, R. J. W., and Pierens, R. K.: J. Chem. Soc (B), 159 (1969).

    Google Scholar 

  51. Davis, K. M. C. and Farmer, M. F.: J. Chem. Soc. (B), 859 (1968).

    Google Scholar 

  52. Bugg, C. E. and Thewalt, U.: Biochem. Biophys. Res. Commun. 37, 623 (1969).

    Article  CAS  Google Scholar 

  53. Bugg, C. E., Thomas, J. M., Sundaralingam, M., and Rao, S. T.: Biopolymers 10, 175 (1971).

    Google Scholar 

  54. Bugg, C. E.: The Purines: Theory and Experiment, Jerusalem Academic Press, Jerusalem 1972, Israel, pp. 178–204.

    Google Scholar 

  55. Iball, J., Morgan, C. H., and Wilson, H. K.: Proc. Roy. Soc. A295, 320 (1966).

    Article  CAS  Google Scholar 

  56. Tougard, P.: Biochim. Biophys. Acta 319, 116 (1973).

    CAS  Google Scholar 

  57. Iball, J., Morgan, C. H., and Wilson, H. R.: Proc. Roy. Soc. A302, 225 (1968).

    Article  Google Scholar 

  58. Harris, D. R. and Macintyre, W. M.: Biophys. J. 4, 203 (1964).

    Article  CAS  Google Scholar 

  59. Pauling, L.: The Nature of the Chemical Bond, Cornell University Press, Ithaca, New York 1964, p. 260.

    Google Scholar 

  60. Sternglanz, H. and Bugg, C. E.: Biochim. Biophys. Acta, in press (1974).

    Google Scholar 

  61. Rahman, A. and Wilson, H. R.: Acta Cryst. B26, 1765 (1970).

    Article  CAS  Google Scholar 

  62. Camerman, N. and Trotter, J.: Acta Cryst. 18, 203 (1965).

    Article  CAS  Google Scholar 

  63. Chandross, R. and Rich, A.: Biopolymers 10, 1795 (1971).

    Article  CAS  Google Scholar 

  64. Fallon III, L.: Acta Cryst. B29, 2549 (1973).

    Article  CAS  Google Scholar 

  65. Voet, D. and Rich, A.: J. Am. Chem. Soc. 91, 3069 (1969).

    Article  CAS  Google Scholar 

  66. Young, D. W. and Morris, E. M.: Acta Cryst. B29, 1259 (1973).

    Article  CAS  Google Scholar 

  67. Haschemeyer, A. E. V. and Sobell, H. M.: Acta Cryst. 18, 525 (1965).

    Article  CAS  Google Scholar 

  68. Tsukihara, T., Ashida, T., and Kakudo, M.: Bull. Chem. Soc. Japan 45, 909 (1972).

    Article  CAS  Google Scholar 

  69. Mizuno, H., Morita, K., Fujiwara, T., and Tomita, K.: Chemistry Letters, 965 (1972); and Mizuno, H.: Doctoral Dissertation Thesis, Faculty of Pharmaceutical Sciences, Osaka University, Japan, 1972.

    Google Scholar 

  70. Mizuno, H., Fujiwara, T., and Tomita, K.: Bull. Chem. Soc. Japan 45, 905 (1972).

    Article  CAS  Google Scholar 

  71. Hawkinson, S. W. and Coulter, C. L.: Acta Cryst. B27, 34 (1971).

    Article  Google Scholar 

  72. Tomita, K., Katz, L., and Rich, A.: J. Mol. Biol. 30, 545 (1967).

    Article  CAS  Google Scholar 

  73. O’Brien, E. J.: Acta Cryst. 23, 92 (1967).

    Article  Google Scholar 

  74. Sobell, H. M.: J. Mol. Biol. 18, 1 (1966).

    Article  CAS  Google Scholar 

  75. Sakore, T. D., Sobell, H. M., Mazza, F., and Kartha, G.: J. Mol. Biol. 43, 385 (1969).

    Article  CAS  Google Scholar 

  76. Tavale, S. S., Sakore, T. D., and Sobell, H. M.: J. Mol. Biol. 43, 375 (1969).

    Article  CAS  Google Scholar 

  77. Mazza, F., Sobell, H. M., and Kartha, G.: J. Mol. Biol. 43, 407 (1969).

    Article  CAS  Google Scholar 

  78. Baklagina, Y. G., Vol’kenshtein, M. V., and Krondraskev, Y. D.: Zh. Strukt. Khim. 7, 399 (1966).

    CAS  Google Scholar 

  79. Motherwell, W. D. S. and Isaacs, N. W.: J. Mol Biol 71, 231 (1972).

    Article  CAS  Google Scholar 

  80. Motherwell, W. D. S., Riva di Sanseverino, L., and Kennard, O.: J. Mol Biol 80, 405 (1973).

    Article  CAS  Google Scholar 

  81. Caillet, J. and Claverie, P.: Biopolymers, in press (1974).

    Google Scholar 

  82. Thewalt, U. and Bugg, C. E.: J. Am. Chem. Soc. 94, 8892 (1972).

    Article  CAS  Google Scholar 

  83. Saenger, W. and Suck, D.: Europ. J. Biochem. 32, 473 (1973).

    Article  CAS  Google Scholar 

  84. Lin, G. H. Y., Sundaralingam, M., and Arora, S. K.: Am. Chem. Soc. 93, 1235 (1971).

    Article  CAS  Google Scholar 

  85. Saenger, W.: Angew. Chem. Internat. Edit. 12, 591 (1973).

    Article  CAS  Google Scholar 

  86. Donohue, J.: J. Mol. Biol 45, 231 (1969).

    Article  CAS  Google Scholar 

  87. Geller, M., Pohorille, A., and Jaworski, A.: Biochim. Biophys. Acta 331, 1 (1973).

    CAS  Google Scholar 

  88. Hammes, G. G. and Park, A. C.: J. Am. Chem. Soc. 91, 956 (1969).

    Article  CAS  Google Scholar 

  89. Kulevsky, N. and Froelich, P. M.: J. Am. Chem. Soc. 89, 4839 (1967).

    Article  CAS  Google Scholar 

  90. Bugg, C. E. and Thewalt, U.: J. Am. Chem. Soc. 92, 7441 (1970).

    Article  CAS  Google Scholar 

  91. Shefter, E.: J. Pharm. Sci. 57, 1157 (1968).

    Article  CAS  Google Scholar 

  92. Subramanian, E., Madden, J. J., and Bugg, C. E.: Biochem. Biophys. Res. Commun. 50, 691 (1973).

    Article  CAS  Google Scholar 

  93. Bugg, C. E. and Thewalt, U.: Acta Cryst., in press (1974).

    Google Scholar 

  94. Thewalt, U., Bugg, C. E., and Marsh, R. E.: Acta Cryst. B26, 1089 (1970).

    Article  CAS  Google Scholar 

  95. LePage, G. A. and Junga, I. G.: Cancer Res. 23, 739 (1963).

    CAS  Google Scholar 

  96. LePage, G. A.: Cancer Res. 20, 403 (1960).

    CAS  Google Scholar 

  97. LePage, G. A. and Jones, M.: Cancer Res. 21, 1590 (1961).

    CAS  Google Scholar 

  98. Adams, D. H.: Biochem. J. 89, 240 (1963).

    CAS  Google Scholar 

  99. Beikirch, H. H. and Lezius, A. G.: Eur. J. Biochem. 27, 381 (1972).

    Article  CAS  Google Scholar 

  100. Faerber, P., Scheit, K. H., and Sommer, H.: Eur. J. Biochem. 27, 109 (1972).

    Article  CAS  Google Scholar 

  101. Scheit, K. H. and Gaertner, E.: Biochim. Biophys. Acta 182, 10 (1969).

    CAS  Google Scholar 

  102. Bahr, W., Faerber, P., and Scheit, K. H.: Eur. J. Biochem. 33, 535 (1973).

    Article  CAS  Google Scholar 

  103. Lezius, A. G. and Domin, E.: Nature New Biol. 244, 169 (1973).

    CAS  Google Scholar 

  104. Simuth, J., Scheit, K. H., and Gottschalk, E. M.: Biochim. Biophys. Acta 204, 371 (1970).

    CAS  Google Scholar 

  105. Kikugawa, K., Iizuka, K., and Ichino, M., J. Med. Chem. 16, 358 (1973).

    Article  CAS  Google Scholar 

  106. Fleysher, M. H.: J. Med. Chem. 15, 187 (1972).

    Article  CAS  Google Scholar 

  107. McLennan, B. D. and Pater, A.: Can. J. Biochem. 51, 1123 (1973).

    CAS  Google Scholar 

  108. Grindey, G. B., Divekar, A. Y., and Hakala, M. T.: Cancer Res. 33, 2459 (1973).

    CAS  Google Scholar 

  109. Fain, J. N.: Mol. Pharmacol. 9, 595 (1973).

    CAS  Google Scholar 

  110. Thewalt, U. and Bugg, C. E.: Acta Cryst B28, 1767 (1972).

    Article  CAS  Google Scholar 

  111. Bugg, C. E. and Thewalt, U.: Biochim. Biophys. Res. Commun. 46, 779 (1972).

    Article  CAS  Google Scholar 

  112. McMullan, R. K. and Sundaralingam, M.: J. Am. Chem. Soc. 93, 7050 (1971).

    Article  CAS  Google Scholar 

  113. Parthasarathy, R., Ohrt, J., and Chheda, G. B.: Paper G9, American Crystallographic Association Meeting, Jan. 14, 1973; and private communication.

    Google Scholar 

  114. Sternglanz, H. and Bugg, C. E.: Biochim. Biophys. Acta 308, 1 (1973).

    CAS  Google Scholar 

  115. Sternglanz, H. and Bugg, C. E.: Science 182, 833 (1973).

    Article  CAS  Google Scholar 

  116. Berthod, H. and Pullman, B.: Compt. Rend. Acad. Sci. Paris D276, 1767 (1973).

    CAS  Google Scholar 

  117. Cook, W. J. and Bugg, C. E.: J. Pharm. Sci., in press (1974).

    Google Scholar 

  118. Gefter, M. L. and Russell, R. L.: J. Mol. Biol. 39, 145 (1969).

    Article  CAS  Google Scholar 

  119. Fittler, F. and Hall, R. H.: Biochem. Biophys. Res. Commun. 25, 441 (1966).

    Article  CAS  Google Scholar 

  120. Bloch, A., Mihich, E., Nichol, C. A., Robins, R. K., and Whistler, R. H.: Proc. Am. Ass. Cancer Res. 7, 7 (1966).

    Google Scholar 

  121. Ikehara, M., Tazawa, J., and Fukui, T.: Biochem. 8, 736 (1969).

    Article  CAS  Google Scholar 

  122. Kapuler, A. M. and Spiegelman, S.: Proc. Nat. Acad. Sci. 66, 539 (1970).

    Article  CAS  Google Scholar 

  123. Kapuler, A. M., Monny, C., and Michelson, A. M.: Biochim. Biophys. Acta 217, 18 (1970).

    CAS  Google Scholar 

  124. Donohue, J. and Trueblood, K. N.: J. Mol. Biol. 2, 363 (1960).

    Article  CAS  Google Scholar 

  125. Sundaralingam, M.: Biopolymers 7, 821 (1969).

    Article  CAS  Google Scholar 

  126. Rao, S. T. and Sundaralingam, M.: J. Am. Chem. Soc. 92, 4963 (1970)

    Article  CAS  Google Scholar 

  127. Hart, P. A. and Davis, J. P.: J. Am. Chem. Soc. 91, 512 (1969).

    Article  CAS  Google Scholar 

  128. Barry, C. D., Ylasel, J. A., North, A. C. T., Williams, R. J. P., and: Xavier, A. V. Biochim. Biophys. Acta 262, 101 (1972).

    CAS  Google Scholar 

  129. Rogers, G. T. and Ulbricht, T. L. V.: Biochem. Biophys. Res. Commun. 39, 419 (1970).

    Article  CAS  Google Scholar 

  130. Haschemeyer, A. E. V. and Rich, A.: J. Mol. Biol. 27, 369 (1967).

    Article  CAS  Google Scholar 

  131. Lakshminarayanan, A. V. and Sasisekharan, V.: Biochim. Biophys. Acta 204, 49 (1970).

    CAS  Google Scholar 

  132. Berthod, H. and Pullman, B.: Biochim. Biophys. Acta 232, 595 (1971).

    CAS  Google Scholar 

  133. Kang, S.: J. Mol. Biol. 58, 297 (1971).

    Article  CAS  Google Scholar 

  134. Miles, D. W., Townsend, L. B., Robins, M. J., Robins, R. K., Inskeep, W. H., and Eyring, H.: J. Am. Chem. Soc. 93, 1600 (1971).

    Article  CAS  Google Scholar 

  135. Gromova, E. S., Guschlbauer, W., and Holy, A.: FEBS Letters 26, 176 (1972).

    Article  CAS  Google Scholar 

  136. Michelson, A. M., Monny, C., and Kapuler, A. M.: Biochim. Biophys. Acta 217, 7 (1970).

    CAS  Google Scholar 

  137. Tavale, S. S. and Sobell, H. M.: J. Mol. Biol. 48. 109 (1970).

    Article  CAS  Google Scholar 

  138. Sternglanz, H., Thomas, J. M., and Bugg, C. E.: to be published.

    Google Scholar 

  139. Prusiner, P. and Sundaralingam, M.: Acta Cryst. B29, 2328 (1973).

    Article  CAS  Google Scholar 

  140. Sprang, S. and Sundaralingam, M.: Acta Cryst. B29, 1910 (1973).

    Article  CAS  Google Scholar 

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  1. Dept. of Biochemistry and Institute of Dental Research, University of Alabama in Birmingham, University Station, Birmingham, Ala., 35294, USA

    Charles E. Bugg & Helene Sternglanz

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  1. Charles E. Bugg
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  1. Department of Organic Chemistry, The Hebrew University, Jerusalem, Israel

    Ernst D. Bergmann

  2. Institut de Biologie Physico-Chimique (Fondation Edmond de Rothschild), Université de Paris, Paris, France

    Bernard Pullman

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Bugg, C.E., Sternglanz, H. (1974). Structural Properties of Purine and Pyrimidine Analogs. In: Bergmann, E.D., Pullman, B. (eds) Molecular and Quantum Pharmacology. The Jerusalem Symposia on Quantum Chemistry and Biochemistry, vol 7. Springer, Dordrecht. https://doi.org/10.1007/978-94-010-1758-9_34

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