Structure-activity relationship of S-trityl-L-cysteine analogues as inhibitors of the human mitotic kinesin Eg5

Journal of Medicinal Chemistry

Volumn 51, Issue 5, 2008, Pages 1115-1125

  DeBonis, Salvatore ^a   Skoufias, Dimitrios A ^a   Indorato, Rose Laure ^a   Liger, François ^b   Marquet, Bernard ^b   Laggner, Christian ^c   Joseph, Benoît ^b   Kozielski, Frank ^d  

^a INSTITUT DE BIOLOGIE STRUCTURALE   (France)

^b UNIVERSITÉ LYON 1   (France)

^c UNIVERSITY OF INNSBRUCK   (Austria)

^d BEATSON INSTITUTE FOR CANCER RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

(1,1 DIPHENYLETHYL)CYSTEINE; (1,1 DIPHENYLPENTYL)CYSTEINE; (1,1 DIPHENYLPROPYL)CYSTEINE; (2 METHYL 1,1 DIPHENYLPROPYL)CYSTEINE; 3 (TRITYLMERCAPTO)PROPYLAMINE; 4 (TRITYLMERCAPTO)BUTYLAMINE; ANTINEOPLASTIC AGENT; EG5 PROTEIN; KINESIN; O(TRITYL)SERINE; UNCLASSIFIED DRUG; [CYCLOHEXYL(DIPHENYL)METHYL]CYSTEINE;

ANTINEOPLASTIC ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG INHIBITION; FLOW CYTOMETRY; HUMAN; HUMAN CELL; IN VITRO STUDY; MITOSIS INHIBITION; STRUCTURE ACTIVITY RELATION;

EID: 41649110829     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm070606z     Document Type: Article

References (43)

1. Zhu, C.; Zhao, J.; Bibikova, M.; Leverson, J. D.; Bossy-Wetzel, E.; Fan, J. B.; Abraham, R. T.; Jiang, W. Functional analysis of human microtubule-based motor proteins, the kinesins and dyneins, in mitosis/cytokinesis using RNA interference (RNAi). Mol. Biol. Cell 2005, 16, 3187-3199.
2. Wood, K. W.; Cornwell, W. D.; Jackson, J. R. Past and future of the mitotic spindle as an oncology target. Curr. Opin. Pharmacol. 2001, 1, 370-377.
3. Miyamoto, D. T.; Perlman, Z. E.; Mitchison, T. J.; Shirasu-Hiza, M. Dynamics of the mitotic spindle-potential therapeutic targets. Prog. Cell Cycle Res. 2003, 5, 349-360.
4. Bergnes, G.; Brejc, K.; Belmont, L. Mitotic kinesins: prospects for antimitotic drug discovery. Curr. Top. Med. Chem. 2005, 5, 127-145.
5. cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 1995, 83, 1159-1169.
6. Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.; Mitchison, T. J. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science 1999, 286, 971-974.
7. Nakazawa, J.; Yajima, J.; Usui, T.; Ueki, M.; Takatsuki, A.; Imoto, M.; Toyoshima, Y. Y.; Osada, H. A novel action of terpendole E on the motor activity of mitotic kinesin Eg5. Chem. Biol. 2003, 10, 131-137.
8. Hotha, S.; Yarrow, J. C.; Yang, J. G.; Garrett, S.; Renduchintala, K. V.; Mayer, T. U.; Kapoor, T. M. HR22C16: A potent small-molecule probe for the dynamics of cell division. Angew. Chem., Int. Ed. 2003, 42, 2379-2382.
9. DeBonis, S.; Skoufias, D.; Robin, G.; Lebeau, L.; Lopez, R.; Margolis, R.; Wade, R. H.; Kozielski, F. In vitro screening for inhibitors of the human mitotic kinesin, Eg5, with antimitotic and antitumor activity. Mol. Cancer Ther. 2004, 3, 1079-1090.
10. Sakowicz, R.; Finer, J. T.; Beraud, C.; Crompton, A.; Lewis, E.; Fritsch, A.; Lee, Y.; Mak, J.; Moody, R.; Turincio, R.; Chabala, J. C.; Gonzales, P.; Roth, S.; Weitman, S.; Wood, K. W. Antitumor activity of a kinesin inhibitor. Cancer Res. 2004, 64, 3276-3280.
11. Gartner, M.; Sunder-Plassmann, N.; Seiler, J.; Utz, M.; Vernos, I.; Surrey, T.; Giannis, A. Development and biological evaluation of potent and specific inhibitors of mitotic kinesin Eg5. ChemBioChem 2005, 6, 1173-1177.
12. Sunder-Plassmann, N.; Sarli, V.; Gartner, M.; Utz, M.; Seiler, J.; Huemmer, S.; Mayer, T. U.; Surrey, T.; Giannis, A. Synthesis and biological evaluation of new tetrahydro-beta-carbolines as inhibitors of the mitotic kinesin Eg5. Bioorg. Med. Chem. 2005, 13, 6094-6111.
13. Tao, W.; South, V. J.; Zhang, Y.; Davide, J. P.; Farrel, L.; Kohl, N. E.; Sepp-Lorenzino, L.; Lobell, R. B. Induction of apoptosis by an inhibitor of the mitotic kinesin KSP requires both activation of the spindle assembly checkpoint and mitotic slippage. Cancer Cell 2005, 8, 49-59.
14. Cox, C. D.; Breslin, M. J.; Mariano, B. J.; Coleman, P. J.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Huber, H. E.; Kohl, N. E.; Torrent, M.; Yan, Y.; Kuo, L. C.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part 1: The discovery of 3,5-diaryl-4,5-dihydropyrazoles as potent and selective inhibitors of the mitotic kinesin KSP. Bioorg. Med. Chem. Lett. 2005, 15, 2041-2045.
15. Pauli, K. D.; Lin, C. M.; Malspeis, L.; Hamel, E. Identification of novel antimitotic agents at the tubulin level by computer-assisted evaluation of differential cytotoxicity data. Cancer Res. 1992, 52, 3892-3900.
16. Skoufias, D. A.; Debonis, S.; Lebeau, L.; Crevel, I.; Cross, R.; Wade, R. H.; Hackney, D. D.; Kozielski, F. S-Trityl-L-cysteine is a reversible, tight binding inhibitor of human Eg5 that specifically blocks mitotic progression. J. Biol. Chem. 2006, 281, 17559-17569.
17. Xiao, D.; Pinto, J. T.; Gunderson, G. F.; Weinstein, I. B. Effects of a series of organosulfur compounds on mitotic arrest and induction of apoptosis in colon cancer cells. Mol. Cancer Ther. 2005, 4, 1388-1398.
18. Brier, S.; Lemaire, D.; DeBonis, S.; Forest, E.; Kozielski, F. Identification of the binding region of a new potent inhibitor of the mitotic kinesin Eg5. Biochemistry 2004, 43, 13072-13082.
19. (a) Guijarro, D.; Mancheno, B; Yus, M. C-O dilithiated diarylmethanols: Easy and improved preparation by naphthalene-catalysed lithiation of diaryl ketones and reactivity toward electrophiles. Tetrahedron 1993, 49, 1327-1334.
20. (b) Guijarro, D.; Guillena, G.; Mancheno, B; Yus, M. Direct transformation of dialkyl sulfates into alkyllithium reagents by a naphthalene-catalysed lithiation. Tetrahedron 1994, 50, 3427-3436.
21. (a) Hatano, M.; Matsumura, T.; Ishihara, K. Highly alkyl-selective addition to ketones with magnesium ate complexes derived from Grignard reagents. Org. Lett. 2005, 7, 573-576.
22. (b) Hatano, M.; Suzuki, S.; Ishihara, K. Highly efficient alkylation to ketones and aldimines with Grignard reagents catalyzed by zinc(II) chloride. J. Am. Chem. Soc. 2006, 128, 9998-9999.
23. Koenig, W.; Geiger, R.; Siedel, W. New sulfur protective groups for cysteine. Chem. Ber. 1968, 101, 681-699.
24. α(ω-thioalkyl)amino acid building units and their incorporation in backbone cyclic disulfide and thioetheric bridged peptides. J. Pept. Res. 2001, 58, 527-539.
25. Zee-Cheng, K.-Y.; Cheng, C. C. Experimental antileukemic agents. Preparation and structure-activity study of S-tritylcysteine and related compounds. J. Med. Chem. 1970, 13, 414-418.
26. Ogo, N.; Oishi, S.; Matsuno, K.; Sawada, J.; Fujii, N.; Asai, A. Synthesis and biological evaluation of L-cysteine derivatives as mitotic kinesin inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 3921-3924.
27. Berman, H. M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T. N.; Weissig, H.; Shindyalov, I. N.; Bourne, P. E. The Protein Data Bank. Nucleic Acids Res. 2000, 28, 235-242.
28. Cox, C. D.; Torrent, M.; Breslin, M. J.; Mariano, B. J.; Whitman, D. B.; Coleman, P. J.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Schaber, M. D.; Lobell, R. B.; Tao, W.; South, V. J.; Kohl, N. E.; Yan, Y.; Kuo, L. C.; Prueksaritanont, T.; Slaughter, D. E.; Li, C.; Mahan, E.; Lu, B.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP. Bioorg. Med. Chem. Lett. 2006, 16, 3175-3179.
29. Tarby, C. M.; Kaltenbach, R. F., 3rd; Huynh, T.; Pudzianowski, A.; Shen, H.; Ortega-Nanos, M.; Sheriff, S.; Newitt, J. A.; McDonnell, P. A.; Burford, N.; Fairchild, C. R.; Vaccaro, W.; Chen, Z.; Borzilleri, R. M.; Naglich, J.; Lombardo, L. J.; Gottardis, M.; Trainor, G. L.; Roussell, D. L. Inhibitors of human mitotic kinesin Eg5: Characterization of the 4-phenyl- tetrahydroisoquinoline lead series. Bioorg. Med. Chem. Lett. 2006, 16, 2095-2100.
30. Kim, K. S.; Lu, S.; Cornelius, L. A.; Lombardo, L. J.; Borzilleri, R. M.; Schroeder, G. M.; Sheng, C.; Rovnyak, G.; Crews, D.; Schmidt, R. J.; Williams, D. K.; Bhide, R. S.; Traeger, S. C.; McDonnell, P. A.; Mueller, L.; Sheriff, S.; Newitt, J. A.; Pudzianowski, A. T.; Yang, Z.; Wild, R.; Lee, F. Y.; Batorsky, R.; Ryder, J. S.; Ortega-Nanos, M.; Shen, H.; Gottardis, M.; Roussell, D. L. Synthesis and SAR of pyrrolotriazine-4-one based Eg5 inhibitors. Bioorg. Med. Chem. Lett. 2006, 16, 3937-3942.
31. Yan, Y.; Sardana, V.; Xu, B.; Homnick, C.; Halczenko, W.; Buser, C. A.; Schaber, M.; Hartman, G. D.; Huber, H. E.; Kuo, L. C. Inhibition of a mitotic motor protein: Where, how, and conformational consequences. J. Mol. Biol. 2003, 335, 547-554.
32. Garcia-Saez, I.; DeBonis, S.; Lopez, R.; Trucco, F.; Rousseau, B.; Thuéry, P.; Kozielski, F. Structure of human Eg5 in complex with a new monastrol-based inhibitor bound in the (R)-configuration. J. Biol. Chem. 2007, 282, 9740-9747.
33. Finer, J. T.; Chabala, J. C.; Lewis, E. Preparation of triphenylmethane as kinesin KSP inhibitors. PCT Int. Appl. WO 02/056880 A1. 2002; Chem. Abstr. 137, 124985.
34. Dothager, R. S.; Putt, K. S.; Allen, B. J.; Leslie, B. J.; Nesterenko, V.; Hergenrother, P. J. Synthesis and identification of small molecules that potently induce apoptosis in melanoma cells through G1 cell cycle arrest. J. Am. Chem. Soc. 2005, 127, 8686-8696.
35. Coleman, P. J.; Schreier, J. D.; Cox, C. D.; Fraley, M. E.; Garbaccio, R. M.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Rickert, K.; Tao, W.; Diehl, R. E.; South, V. J.; Davide, J. P.; Kohl, N. E.; Yan, Y.; Kuo, L.; Prueksaritanont, T.; Li, C.; Mahan, E. A.; Fernandez-Metzler, C.; Salata, J. J.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part 6: Design and synthesis of 3,5-diaryl-4,5-dihydropyrazole amides as potent inhibitors of the mitotic kinesin KSP. Bioorg. Med. Chem. Lett. 2007, 17, 5390-5395.
36. Roecker, A. J.; Coleman, P. J.; Mercer, S. P.; Schreier, J. D.; Buser, C. A.; Walsh, E. S.; Hamilton, K.; Lobell, R. B.; Tao, W.; Diehl, R. E.; South, V. J.; Davide, J. P.; Kohl, N. E.; Yan, Y.; Kuo, L. C.; Li, C.; Fernandez-Metzler, C.; Mahan, E. A.; Prueksaritanont, T.; Hartman, G. D. Kinesin spindle protein (KSP) inhibitors. Part 8: Design and synthesis of 1,4-diaryl-4,5- dihydropyrazoles as potent inhibitors of the mitotic kinesin KSP. Bioorg. Med. Chem. Lett. 2007, 17, 5677-5682.
37. Brier, S.; Lemaire, D.; DeBonis, S.; Forest, E.; Kozielski, F. Molecular dissection of the inhibitor binding pocket of mitotic kinesin Eg5 reveals mutants that confer resistance to antimitotic agents. J. Mol. Biol. 2006, 360, 360-376.
38. Catalyst 4.11; Accelrys: San Diego, CA, 2005.
39. Sybyl 7.2; Tripos, Inc.: St. Louis, MO, 2006.
40. Gold 3.2; The Cambridge Crystallographic Data Centre: Cambridge, U.K., 2007.
41. (a) Wolber, G.; Dornhofer, A.; Langer, T. Efficient overlay of small molecules using 3-D pharmacophores. J. Comput.-Aided. Mol. Des. 2006, 20, 773-788.
42. (b) Wolber, G.; Langer, T. LigandScout: 3D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J. Chem. Inf. Comput. Sci. 2005, 45, 160-169.
43. (c) LigandScout 2.0; Inte:Ligand GmbH: Vienna, Austria, 2007.