Synthesis of Pyrimidine, Pyran and Pyridine Derivatives and their Biological Evaluation and Molecular Docking Studies as Potential CDK-1 and GSK-3 Inhibitors

Authors

  • Dipak C. Patel  The H. N. S. B. Ltd. Science College, Himmatnagar, Gujarat, India

Keywords:

CDK-1, GSK-3, Molecular Docking

Abstract

Thirty five new compounds belonging to pyrimidine, pyran and pyridine classes were synthesized and tested against two protein kinases, CDK-1/cyclin B and GSK-3. Among these compounds, 2-amino-4-(2-butyl-5-chloro-4H-imidazol-4-yl)-6-(4-hydroxyphenyl)pyridine-3-carbonitrile 17d was identified as the most potent inhibitor of these kinases. To identify possible binding modes, docking of the most active compounds into the active sites of CDK-1/cyclin B and GSK-3 was carried out. The molecular modeling studies brought to the fore stereochemistry and nature of the central core ring as major determinants affecting CDK-1/cyclin B and GSK-3 activity.

References

  1. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S (2002) The protein kinase complement of the human genome. Science 298:1912-1934.
  2. Knockaert M, Greengard P, Meijer L (2002) Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol Sci 23:417-425.
  3. Loge C, Testard A, Thiery V, Lozach O, Blairvacq M, Robert JM, Meijer L, Besson T (2008) Novel 9-oxo-thiazolo[5,4-f]quinazoline-2-carbonitrile derivatives as dual cyclin-dependent kinase 1 (CDK1)/glycogen synthase kinase-3 (GSK-3) inhibitors: synthesis, biological evaluation and molecular modeling studies. Eur J Med Chem 43:1469-1477.
  4. Malumbres M, Barbacid M (2005) Mammalian cyclin-dependent kinases. Trends Biochem Sci 30:630-641.
  5. Jope RS, Johnson GV (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29:95-102.
  6. Meijer L, Flajolet M, Greengard P (2004) Pharmacological inhibitors of glycogen synthase kinase 3. Trends Pharmacol Sci 25:471-480.
  7. Soos TJ, Meijer L, Nelson PJ (2006) CDK/GSK-3 inhibitors as a new approach for the treatment of proliferative renal diseases. Drug News Perspect 19:325-328.
  8. (a) Lecler S, Garnier M, Hoessel R, Marko D, Bibb JA (2001) J. Biol. Chem. 276:251; (b) Leost M, Schultz C, Link A, Wu YZ, Biernat J, Mandelkow EM (2000) Eur. J. Biochem., 267:5983.
  9. Sybyl 7.1, Tripos Inc., St. Louis, Missouri, USA.
  10. InsightII v2005L, Accelrys Inc., San Diego, California, USA, XI.
  11. Gold Suite 4, CCDC, Cambridge, UK.
  12. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Res 28:235-242.
  13. Marti-Renom MA, Stuart AC, Fiser A, Sanchez R, Melo F, Sali A (2000) Comparative protein structure modeling of genes and genomes. Annu Rev Biophys Biomol Struct 29:291-325.
  14. Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234:779-815.
  15. Fiser A, Do RK, Sali A (2000) Modeling of loops in protein structures. Protein Sci 9:1753-1773.
  16. Shen MY, Sali A (2006) Statistical potential for assessment and prediction of protein structures. Protein Sci 15:2507-2524.
  17. Luthy R, Bowie JU, Eisenberg D (1992) Assessment of protein models with three-dimensional profiles. Nature 356:83-85.
  18. Gribskov M, McLachlan AD, Eisenberg D (1987) Profile analysis: detection of distantly related proteins. Proc Natl Acad Sci U S A 84:4355-4358.
  19. Gribskov M, Luthy R, Eisenberg D (1990) Profile analysis. Methods Enzymol 183:146-159.
  20. Verma S, Nagarathnam D, Shao J, Zhang L, Zhao J, Wang Y, Li T, Mull E, Enyedy I, Wang C, Zhu Q, Altieri M, Jordan J, Dang TT, Reddy S (2005) Substituted aminobenzimidazole pyrimidines as cyclin-dependent kinase inhibitors. Bioorg Med Chem Lett 15:1973-1977.
  21. Fousteris MA, Papakyriakou A, Koutsourea A, Manioudaki M, Lampropoulou E, Papadimitriou E, Spyroulias GA, Nikolaropoulos SS (2008) Pyrrolo[2,3-a]carbazoles as potential cyclin dependent kinase 1 (CDK1) Inhibitors. Synthesis, biological evaluation, and binding mode through docking simulations. J Med Chem 51:1048-1052.
  22. Mooij WT, Verdonk ML (2005) General and targeted statistical potentials for protein-ligand interactions. Proteins: Struct, Funct, & Bioinfo 61:272-287.
  23. Gehlhaar DK, Verkhivker GM, Rejto PA, Sherman CJ, Fogel DB, Fogel LJ, Freer ST (1995) Molecular recognition of the inhibitor AG-1343 by HIV-1 protease: conformationally flexible docking by evolutionary programming. Chem Biol 2:317-324.
  24. Krammer A, Kirchhoff PD, Jiang X, Venkatachalam CM, Waldman M (2005) LigScore: a novel scoring function for predicting binding affinities. J Mol Graph Model 23:395-407.
  25. Jain AN (1996) Scoring noncovalent protein-ligand interactions: a continuous differentiable function tuned to compute binding affinities. J Comput Aided Mol Des 10:427-440.
  26. Muegge I, Martin YC (1999) A general and fast scoring function for protein-ligand interactions: a simplified potential approach. J Med Chem 42:791-804.
  27. Bohm HJ (1994) The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of known three-dimensional structure. J Comput Aided Mol Des 8:243-256.
  28. Patel DS, Bharatam PV (2008) Selectivity criterion for pyrazolo[3,4-b]pyrid[az]ine derivatives as GSK-3 inhibitors: CoMFA and molecular docking studies. Eur J Med Chem 43:949-957.
  29. Prasanna S, Daga PR, Xie A, Doerksen RJ (2008) Glycogen synthase kinase-3 inhibition by 3-anilino-4-phenylmaleimides: insights from 3D-QSAR and docking. J Comput Aided Mol Des.
  30. Dessalew N, Patel DS, Bharatam PV (2007) 3D-QSAR and molecular docking studies on pyrazolopyrimidine derivatives as glycogen synthase kinase-3 beta inhibitors. J Mol Graph Model 25:885-895.

International Journal of Scientific Research in Science, Engineering and Technology

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Published

2015-02-27

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Volume 1, Issue 1, January-February-2015

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Research Articles

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[1]
Dipak C. Patel "Synthesis of Pyrimidine, Pyran and Pyridine Derivatives and their Biological Evaluation and Molecular Docking Studies as Potential CDK-1 and GSK-3 Inhibitors" International Journal of Scientific Research in Science, Engineering and Technology (IJSRSET), Print ISSN : 2395-1990, Online ISSN : 2394-4099, Volume 1, Issue 1, pp.401-409, January-February-2015.