A New Generation of N-Aryl-N′-(1-alkyl-2-chloroethyl)ureas as Microtubule Disrupters: Synthesis, Antiproliferative Activity, and β-Tubulin Alkylation Kinetics

Journal of Medicinal Chemistry

Volumn 46, Issue 23, 2003, Pages 5055-5063

  Mounetou, Emmanuelle ^a,b   Legault, Jean ^a   Lacroix, Jacques ^a   Gaudreault, René C ^a  

^a Université Laval   (Canada)

^b INSERM   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; BETA TUBULIN; N (4 IODOPHENYL N' (1 METHYL 2 CHLORO)ETHYLUREA; N (4 ISOPROPYL)PHENYL N' (1 METHYL 2 CHLORO)ETHYLUREA; N' 2 CHLOROETHYLUREA DERIVATIVE; UNCLASSIFIED DRUG; UREA DERIVATIVE;

ALKYLATION; ANIMAL CELL; ARTICLE; CONTROLLED STUDY; CYTOTOXICITY; DRUG ACTIVITY; DRUG STRUCTURE; DRUG SYNTHESIS; ENANTIOMER; HUMAN; HUMAN CELL; MICROTUBULE; MITOSIS INHIBITION; MOUSE; NONHUMAN; PROTEIN MODIFICATION; STRUCTURE ACTIVITY RELATION;

EID: 0242267903     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm030908a     Document Type: Article

References (34)

1. Hortobagyi, G. N. Developments in chemotherapy of breast cancer. Cancer 2000, 88, 3073-3079.
2. Giannakakou, P.; Sackett, D.; Fojo, T. Tubulin/microtubules: still a promising target for new chemotherapeutic agents. J. Natl. Cancer Inst. 2000, 92, 182-183.
3. (a) Burns, R.; Surridge, C. Tubulin: conservation and structure. In Microtubules; Hyams, J. S., Lloyd, C. W., Eds.; Wiley-Liss, Inc: New York, 1994; pp 11-35.
4. (b) McIntosh, J. The roles of microtubules in chromosome movement. In Microtubules; Hyams, J. S., Lloyd, C. W., Eds; Wiley-Liss, Inc: New York, 1994; pp 394-412.
5. Downing, K. H.; Nogales, E. Tubulin structure: insights into microtubule properties and functions. Curr. Opin. Struct. Biol. 1998, 8, 785-791.
6. Hastie, S. B. Interactions of colchicines with tubulin. Pharmacol. Ther. 1991, 51, 377-401.
7. Rai, S. S.; Wolff, J. Localization of the vinblastine-binding site on beta-tubulin. J. Biol Chem. 1996, 271, 14707-14711.
8. Cortese, F.; Bhattacharyya, B.; Wolff, J. Podophyllotoxin as a probe for the colchicines binding site of tubulin. J. Biol. Chem. 1977, 521, 1134-1140.
9. Cushman, M.; He, H.; Lin, C. M.; Hamel, E. Synthesis and evaluation of a series of benzylaniline hydrochlorides as potential cytotoxic and antimitotic agents acting by inhibition of tubulin polymerisation. J. Med. Chem. 1993, 36, 2817-2821.
10. Verwej, J.; Clavel, M.; Chevalier, B. Paclitaxel (Taxol) and docetaxel (Taxotere): not simply two of a kind. Ann. Oncol. 1994, 5, 495-505.
11. Kowalski, R. J.; Giannakakou, P.; Hamel, E. Activities of the microtubule-stabilizing agents epothilones A and B with purified tubulin and in cells resistant to paclitaxel (Taxol). J. Biol. Chem. 1997, 272, 2534-2541.
12. ter Haar, E.; Kowalski, R. J.; Hamel, E.; Lin, C. M.; Gunasekera, S. P.; Rosenkranz, H. S.; Day, B. W. Discodermolide, a cytotoxic marine agent that stabilizes microtubules more potently than taxol. Biochemistry 1996, 35, 243-250.
13. Long, B. H.; Carboni, J. M.; Wasserman, A. J.; Cornell, L. A.; Casazza, A. M.; Jensen, P. R. Eleutherobin, a novel cytotoxic agent that induces tubulin polymerization, is similar to paclitaxel (Taxol). Cancer Res. 1998, 58, 1111-1115.
14. Hamel, E. Antimitotic natural products and their interactions with tubulin. Med. Res. Rev. 1996, 16, 207-231.
15. Jordan, M. A. Mechanism of action of antitumor drugs that interact with microtubules and tubulin. Curr. Med. Chem.: Anti-Cancer Agents 2002, 2, 1-17.
16. Dumontet, C. Mechanisms of action and resistance to tubulin-binding agents. Expert Opin. Invest. Drugs 2000, 9, 779-788.
17. Scozzafava, A.; Casini, A.; Supuran, C. T. Targeting cystein residues of biomolecules: new approaches for the design of antiviral and anticancer drugs. Curr. Med. Chem. 2002, 9, 1167-1185.
18. 14C]-acetamide and N,N′-ethylenebis(iodoacetamide). Biochemistry 1981, 20, 4437-4444.
19. Lee, Y. C.; Yaple, R. A.; Baldridge, R.; Kirsch, M.; Himes, R. H. Inhibition of tubulin self assembly in vitro by fluorodinitrobenzene. Biochim. Biophys. Acta 1981, 671, 71-77.
20. Bai, R. L.; Duanmu, C.; Hamel, E. Mechanism of action of the antimitotic drug 2,4-dichlorobenzyl thiocyanate: alkylation of sulfhydryl group(s) of β-tubulin. Biochim. Biophys. Acta 1989, 994, 12-20.
21. Luduena, R. F.; Roach, M. C. Tubulin sulfhydryl groups as probes and targets for antimitotic and antimicrotubule agents. Pharmacol. Ther. 1991, 49, 133-152.
22. Ikeda, Y.; Steiner, M. Sulfhydryls of platelet tubulin: their role in polymerization and colchicine binding. Biochemistry 1978, 17, 3454-3459.
23. Britto, P. J.; Knipling, L.; Wolff, J. The local electrostatic environment determines cysteine reactivity of tubulin. J. Biol. Chem. 2002, 277, 29018-29027.
24. Shan, B.; Medina, J. C.; Santha, E.; Frankmoelle, W. P.; Chou, T. C.; Learned, R. M.; Narbut, M. R.; Stott, D.; Wu, P.; Jaen, J. C.; Rosen, T.; Timmermans, P. B.; Beckmann, H. Selective, covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 5686-5691.
25. Mounetou, E.; Legault, J.; Lacroix, J.; Gaudreault, R. C. Antimitotic antitumor agents: synthesis, structure activity relationships and biological characterization of N-Aryl-N′-(2-chloroethyl)-ureas as new selective alkylating agents. J. Med. Chem. 2001, 44, 694-702.
26. Legault, J.; Gaulin, J. F.; Mounetou, E.; Bolduc, S.; Lacroix, J.; Poyet, P.; Gaudreault, R. Microtubule disruption induced in vivo by alkylation of β-tubulin by 1-aryl-3-(2-chloroethyl)urea, a novel class of antineoplasic soft alkylating agents. Cancer Res. 2000, 60 (4), 985-992.
27. Gaudreault, R.; Alaoui-Jamli, M.; Batist, G.; Béchard, P.; Lacroix, J.; Poyet, P. Lack of cross-resistance to a new cytotoxic arylchloroethylurea in various drug-resistant tumor cells. Cancer Chemother. Pharmacol. 1994, 33, 489-492.
28. Bardos, T.; Datta-Gupta, P.; Hebborn, P.; Triggle, D. J. A study of comparative chemical and biological activities of alkylating agents. J. Med. Chem. 1965, 8, 167-174.
29. Knölker, H. J.; Braxmeier, T.; Schelchtinger, G. Synthesis of symmetrical and unsymmetrical ureas by DMAP-catalyzed reaction of alkyl- and arylamines with di-tert-butyldicarbonate. Synlett 1996, 502-504.
30. Knölker, H. J.; Braxmeier, T. Convenient phosgene-free method for the synthesis and derivatization of enantiopure α-isocyanato carboxylic acid esters. Synlett 1997, 925-928.
31. Schibler, M. J.; Cabral, F. Taxol-dependent mutants of Chinese hamster ovary cells with alterations in α- and β-tubulin. J. Cell Biol. 1986, 102, 1522-1531.
32. Cabral, F.; Sobel, M. E.; Gottesman, M. M. CHO mutants resistant to colchicines, colcemid or grisofulvin have an altered β-tubulin. Cell 1980, 20, 29-36.
33. O'Brien, J.; Wilson, I.; Orton, T.; Pognan, F. Investigation of the Alamar Blue (resazurin) fluorescent dye for the assessment of mammalian cell cytotoxicity. Eur. J. Biochem. 2000, 267, 5421-5426.
34. Laemmli, U.K. Cleavage of structural proteins during assembly of the head of bacteriophage T4. Nature 1970, 227, 680-685.