QSAR Approach in Study of Mutagenicity of Aromatic and Heteroaromatic Amines

  • Marjan VračkoEmail author
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 4)


In this chapter we give an overview on QSAR models for treating the mutagenicity of cyclic amines. An extensive discussion is focused on the topological, E-state, quantum chemical, and empirical descriptors (logP) that are often used in corresponding models. Two case studies are presented in more detail. The conclusion addresses the OECD principles for validation of models that are used for regulatory purposes.

Amines Pyriminoizodiamines Mutagenicity Descriptors Neural network 



(Quantitative) structure–activity relationship


Energy of the highest occupied orbital


Energy of the lowest unoccupied orbital

2D, 3D

Two dimensional, Three dimensional


Organization for economic cooperation and development


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Benigni R, Giuliani A, Franke R, Gruska A (2000) Chem Rev 100:3697 CrossRefGoogle Scholar
  2. 2.
    McCann J, Choi E, Yamasaki E, Ames BN (1975) Proc Natl Acad Sci USA 72:5135 CrossRefGoogle Scholar
  3. 3.
    Zeiger E (2001) Mutat Res 492:29 Google Scholar
  4. 4.
    Dolin PJ (1992) Br J Cancer 65:476 CrossRefGoogle Scholar
  5. 5.
    Vincis P, Pirastu R (1997) Cancer Cause Control 8:346 CrossRefGoogle Scholar
  6. 6.
    Kinosita R (1937) Tr Soc Path Jap 27:665 Google Scholar
  7. 7.
    Benigni R, Giuliani A, Gruska A, Franke R (2003) QSARs for the mutagenicity and carcinogenicity of the aromatic amines. In: Benigni R (ed) Quantitative structure–activity relationship (QSAR) models of mutagens and carcinogens. CRC, Boca Raton FL, p 125 Google Scholar
  8. 8.
    Benigni R (2005) Chem Rev 105:1767 CrossRefGoogle Scholar
  9. 9.
    Klopman G, Frierson MR, Rosenkranz HS (1985) Environ Mutagen 7:625 CrossRefGoogle Scholar
  10. 10.
    Zhang YP, Klopman G, Rosenkranz HS (1993) Environ Mol Mutagen 21:100 CrossRefGoogle Scholar
  11. 11.
    Glende C, Klein M, Schmitt H, Erdinger L, Boche G (2002) Mutat Res 515:15 Google Scholar
  12. 12.
    Debnath AK, Debnath G, Shusterman AJ, Hansh C (1992) Environ Mol Mutagen 19:37 CrossRefGoogle Scholar
  13. 13.
    Garg A, Bhat KL, Bock CW (2002) Dyes Pigments 55:35 CrossRefGoogle Scholar
  14. 14.
    CODESSATM, v20, Semichem, 7204 Mullen, Shawnee KS 66216, USA Google Scholar
  15. 15.
    Gramatica P, Connsonni V, Pavan M (2003) SAR QSAR Environ Res 14:237 CrossRefGoogle Scholar
  16. 16.
    Todeschini R, Consonni V, Mauri A, Pavan M (2002) DRAGON rel 2.1 for Windows, Milano, Italy Google Scholar
  17. 17.
    Todeschini R, Mauri A (2000) DOLPHIN rel 2.1 for Windows, Milano, Italy Google Scholar
  18. 18.
    Leardi R, Boggia R, Terrile M (1992) J Chemom 6:267 CrossRefGoogle Scholar
  19. 19.
    Chung KT, Chen SC, Wong TY, Li YS, Wei CI, Chou MW (2000) Toxicol Sci 56:351 CrossRefGoogle Scholar
  20. 20.
    Hatch FT, Lightstone, Colvin ME (2000) Environ Mol Mutagen 35:279 CrossRefGoogle Scholar
  21. 21.
    Patlewicz G, Rodford R, Walker JD (2003) Environ Toxicol Chem 22:1885 CrossRefGoogle Scholar
  22. 22.
    Votano JR, Parham M, Hall LH, Kier LB, Oloff S, Tropsha A, Xie Q, Tong W (2004) Mutagenesis 19:365 CrossRefGoogle Scholar
  23. 23.
    Lozano JJ, Pastor M, Cruciani G, Gaedt K, Centeno NB, Gago F, Sanz F (2000) J Comput Aid Mol Des 14:341 CrossRefGoogle Scholar
  24. 24.
    Mattioni BE, Kauffman GW, Jurs PC, Custer LL, Durham SK, Pearl GM (2003) J Chem Inf Comput Sci 43:949 CrossRefGoogle Scholar
  25. 25.
    Contrera JF, Matthews EJ, Kruhlak NL, Benz RD (2005) Regul Toxicol Pharmacol 43:313 CrossRefGoogle Scholar
  26. 26.
    Zupan J, Vračko M, Novič M (2000) Acta Chim Slov 47:11 Google Scholar
  27. 27.
    Todeschini R, Consonni V (2000) The handbook of molecular descriptors. Wiley, New York CrossRefGoogle Scholar
  28. 28.
    Schuur JH, Selzer P, Gasteiger J (1996) J Chem Inf Comput Sci 36:334 CrossRefGoogle Scholar
  29. 29.
    Diudea MV (ed) (2001) QSPR/QSAR studies by molecular descriptors. Nova Science, Hungtington, New York Google Scholar
  30. 30.
    Basak SC, Mills D (2001) SAR QSAR Environ Res 12:481 CrossRefGoogle Scholar
  31. 31.
    Wiener H (1947) J Am Chem Soc 69:2636 CrossRefGoogle Scholar
  32. 32.
    Balaban A (2001) A personal view about topological indices for QSAR/QSPR. In: Diudea MV (ed) QSPR/QSAR studies by molecular descriptors. Nova Science, Hungtington, New York Google Scholar
  33. 33.
    Devillers J, Balaban AT (eds) (1999) Topological indices and related descriptors in QSAR and QSPR. Gordon and Breach, Reading, UK Google Scholar
  34. 34.
    Randić M (1998) Topological indices. In: Schleyer PvR, Allinger NL, Clark T, Gasteiger J, Kollman PA, Schaefer III HF, Schreiner PR (eds) Encyclopedia of computational chemistry. Wiley, Chichester Google Scholar
  35. 35.
    Netzeva TI (2004) Whole molecule and atom-based topological descriptors. In: Cronin MTD (ed) Predicting chemical toxicity and fate. CRC, Boca Raton FL Google Scholar
  36. 36.
    Randič M (1975) J Am Chem Soc 97:6609 CrossRefGoogle Scholar
  37. 37.
    Randič M (2001) J Mol Graphics Modelling 20:19 CrossRefGoogle Scholar
  38. 38.
    Kier LB, Hall LH (1976) J Pharm Sci 65:1806 CrossRefGoogle Scholar
  39. 39.
    Rose K, Hall LH, Kier LB (2002) J Chem Inf Comput Sci 42:651 CrossRefGoogle Scholar
  40. 40.
    Katritzky AR, Lobanov VS, Karelson M (1994) CODESSA Reference manual 2.0, Gainesville Google Scholar
  41. 41.
    Rohrbaugh RH, Jurs PC (1987) Anal Chim Acta 199:99 CrossRefGoogle Scholar
  42. 42.
    Randić M, Razinger M (1997) On characterization of 3D molecular structure. In: Balaban AT (ed) From chemical topology to three-dimensional structure. Plenum, New York Google Scholar
  43. 43.
    Thouless DJ (1972) The quantum mechanics of many-body systems. Academic, New York Google Scholar
  44. 44.
    Schaefer III HF (1977) Methods of electronic structure theory. Plenum, New York Google Scholar
  45. 45.
    Hehre WJ, Radom L, Schleyer PR, Pople JA (1986) Ab initio molecular orbital theory. Wiley, New York Google Scholar
  46. 46.
    Murrell JN, Herget AJ (1972) Semi-empirical self-consistent-field-molecular theory of molecules. Wiley, New York Google Scholar
  47. 47.
    Koopmans T (1934) Physica 1:104 CrossRefGoogle Scholar
  48. 48.
    Schüürmann G (2004) Quantum chemical descriptors in structure–activity relationships – calculation, interpretation, and comparison of methods. In: Cronin MTD (ed) Predicting chemical toxicity and fate. CRC, Boca Raton FL Google Scholar
  49. 49.
    Hansch C, Maloney PP, Fujita T, Muir RM (1962) Nature 194:178 CrossRefGoogle Scholar
  50. 50.
    Silverman RB (2004) The organic chemistry of drug design and drug action. Elsevier, Amsterdam, p 55 Google Scholar
  51. 51.
    Medić-Šarić M, Mornar A, Badovinac-Črbjević T, Jasprica I (2004) Croat Chem Acta 1–2:367 Google Scholar
  52. 52.
    Petrauskas AA, Kolovanov EA (2000) Perspect. Drug Discovery and Design 19:99 CrossRefGoogle Scholar
  53. 53.
    Eros D, Kovesdi I, Orfi L, Takacs-Novak K, Acsady G, Keri G (2002) Current Med Chem 9:1819 Google Scholar
  54. 54.
    Schuur JH, Selzer P, Gasteiger J (1996) J Chem Inf Comput Sci 36:334 CrossRefGoogle Scholar
  55. 55.
    Zupan J, Vračko M, Novič M (2000) Acta Chim Slov 47:19 Google Scholar
  56. 56.
    Hemmer CM, Gasteiger J (2000) Anal Chim Acta 420:145 CrossRefGoogle Scholar
  57. 57.
    Bursi R, Dao T, Wijk Tv, Gooyer Md, Kellenbach E, Verwer P (1999) J Chem Inf Comput Sci 39:861 CrossRefGoogle Scholar
  58. 58.
    Cramer RD, DePriest SA, Patterson DE, Hecht P (1993) The developing practice of comparative molecular field analysis. In: Kubinyi H (ed) 3D QSAR in drug design theory, methods and applications, vol 1. ESCOM Leiden 443–485 Google Scholar
  59. 59.
  60. 60.
    Leardi R (ed) (2003) Nature-inspired methods in chemometrics: Genetic algorithms and artificial neural networks. Elsevier, Amsterdam Google Scholar
  61. 61.
    Helma C (ed) (2005) Predictive toxicology. Taylor Francis, Boca Raton FL Google Scholar
  62. 62.
    Zupan J, Gasteiger J (1999) Neural networks in chemistry and drug design. Wiley, Weinheim Google Scholar
  63. 63.
    Vračko M (2005) Curr Comput-Aided Drug Des 1:73 CrossRefGoogle Scholar
  64. 64.
    Panek JJ, Jezierska A, Vračko M (2005) J Chem Inf Model 45:264 CrossRefGoogle Scholar
  65. 65.
    Spycher S, Pellegrini E, Gasteiger J (2005) J Chem Inf Model 45:200 CrossRefGoogle Scholar
  66. 66.
    Roncaglioni A, Novič M, Vračko M, Benfenati E (2004) J Chem Inf Comput Sci 44:300 CrossRefGoogle Scholar
  67. 67.
    Jezierska A, Vračko M, Basak SC (2004) Mol Divers 8:371 CrossRefGoogle Scholar
  68. 68.
    Shirai T, Sano M, Tamano S, Takahashi S, Hirose T, Futakuchi M, Hasegawa R, Imaida K, Matsumoto K-I, Wakabayashi K, Sugimura T, Ito N (1997) Cancer Res 57:195 Google Scholar
  69. 69.
    Felton JS, Knize MG, Hatch FT, Tanga MJ, Colvin ME (1999) Cancer Letters 143:127 CrossRefGoogle Scholar
  70. 70.
    Cash GG (2001) Mutat Res Genet Toxicol Environ Mutagen 491:31 CrossRefGoogle Scholar
  71. 71.
    Cash GG, Anderson B, Mayo K, Bogaczyk S, Tunkel J (2005) Mutat Res 585:170 Google Scholar
  72. 72.
    Maran U, Karelson M, Katritzky AR (1999) Quant Struct-Act Relat 18:3 CrossRefGoogle Scholar
  73. 73.
    Karelson M, Sild S, Maran U (2000) Mol Simul 24:229 CrossRefGoogle Scholar
  74. 74.
    Basak SC, Mills D (2001) SAR QSAR Environ Res 12:481 CrossRefGoogle Scholar
  75. 75.
    Basak SC, Mills D, Balaban AT, Gute BD (2001) J Chem Inf Comput Sci 41:671 CrossRefGoogle Scholar
  76. 76.
    Basak SC, Gute BD, Grunwald GD (1998) Relative effectiveness of topological, geometrical, and quantum chemical parameters in estimating mutagenicity of chemicals. In: Chen F, Schüürmann G (eds) Proceedings of the quantitative structure–activity relationships in environmental sciences. VII SETAC, Pensacola FL, p 245 Google Scholar
  77. 77.
    Frisch MJ, Trucks GW, Schlegel HB, Gill PMW, Johnson BG, Robb MA, Cheeseman JR, Keith T, Petersson GA, Montgomery JA, Raghavachari K, Al-Laham MA, Zakrzewski VG, Ortiz JV, Foresman JB, Peng CY, Ayala PY, Chen W, Wong MW, Andres JL, Replogle ES, Gomperts R, Martin RL, Fox DJ, Binkley JS, Defrees DJ, Baker J, Stewart JP, Head-Gordon M, Gonzalez C, Pople JA (1995) GAUSSIAN 94. Gaussian Inc, Pittsburgh, PA Google Scholar
  78. 78.
    Vračko M, Szymoszek A, Barbieri P (2004) J Chem Inf Comput Sci 44:352 CrossRefGoogle Scholar
  79. 79.
    Valkova I, Vračko M, Basak SC (2004) Anal Chim Acta 509:179 CrossRefGoogle Scholar
  80. 80.
    Vračko M, Mills D, Basak SC (2004) Environ Toxicol Pharmacol 16:25 CrossRefGoogle Scholar
  81. 81.
    MOLCONN-Z (2000) Version 3.5. Hall Associates, Quincy, MA Google Scholar
  82. 82.
    SAS Institute(1988) Release 6.03. Cary, NC Google Scholar
  83. 83.
    Golbraikh A, Tropsha A (2003) J Comput-aided Mol Des 16:357 CrossRefGoogle Scholar
  84. 84.
    Golbraikh A (2000) J Chem Inf Comput Sci 40:414 CrossRefGoogle Scholar
  85. 85.
    OECD series on testing and assessment, Number 12. ENV/JM/MONO(99)2 Google Scholar
  86. 86.
    The principles for establishing the status of development and validation of (quantitative) structure–activity relationships [(Q)SARs]. OECD document ENV/JM/TG(2004)27 Google Scholar
  87. 87.
    Snyder RD, Smith MD (2005) Drug Discov Today 10:1119 CrossRefGoogle Scholar

Authors and Affiliations

  1. 1.Kemijski inštitut/National Institute of ChemistryLjubljanaSlovenia

Personalised recommendations