Incorporation of fluorinated phenylalanine generates highly specific inhibitor of proteasome's chymotrypsin-like sites

Journal of Medicinal Chemistry

Volumn 53, Issue 5, 2010, Pages 2319-2323

  Geurink, Paul P ^a   Liu, Nora ^a   Spaans, Michiel P ^a   Downey, Sondra L ^b   Van Den Nieuwendijk, Adrianus M C H ^a   Van Der Marel, Gijsbert A ^a   Kisselev, Alexei F ^b   Florea, Bogdan I ^a   Overkleeft, Herman S ^a  

^a LEIDEN UNIVERSITY   (Netherlands)

^b DARTMOUTH MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; CHYMOTRYPSIN; PHENYLALANINE DERIVATIVE; PROTEASOME INHIBITOR;

ARTICLE; CONTROLLED STUDY; DRUG POTENCY; DRUG SELECTIVITY; DRUG STRUCTURE; ENZYME ACTIVE SITE; FLUORINATION; HUMAN; HUMAN CELL;

CATALYTIC DOMAIN; CHYMOTRYPSIN; CYSTEINE PROTEINASE INHIBITORS; INHIBITORY CONCENTRATION 50; PHENYLALANINE; PROTEASOME ENDOPEPTIDASE COMPLEX; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77949343548     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm9015685     Document Type: Article

References (27)

1. Borissenko, L.; Groll, M. 20S Proteasome and its inhibitors: crystallographic knowledge for drug development. Chem. Rev. 2007, 107, 687-717.
2. Kisselev, A. F.; Goldberg, A. L. Proteasome inhibitors: from research tools to drug candidates. Chem. Biol. 2001, 8, 739-758.
3. Adams, J.; Behnke, M.; Chen, S. W.; Cruickshank, A. A.; Dick, L. R.; Grenier, L.; Klunder, J. M.; Ma, Y. T.; Plamondon, L.; Stein, R. L. Potent and selective inhibitors of the proteasome: Dipeptidyl boronic acids. Bioorg. Med. Chem. Lett. 1998, 8, 333-338. For the structure of compound 8, see SI.
4. Examples of selective inhibitors for (a) β1: Van Swieten, P. F.; Samuel, E.; Hernández, R. O.; van den Nieuwendijk, A. M. C. H.; Leeuwenburgh, M. A.; van der Marel, G. A.; Kessler, B. M.; Overkleeft, H. S.; Kisselev, A. F. A cell-permeable inhibitor and activity-based probe for the caspase-like activity of the proteasome. Bioorg. Med. Chem. Lett. 2007, 17, 3402-3405;
5. (b) β2: Nazif, T.; Bogyo, M. Global analysis of proteasomal substrate specificity using positional-scanning libraries of covalent inhibitors. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 2967-2972;
6. (c) β5: Elofsson, M.; Splittgerber, U.; Myung, J.; Mohan, R.; Crews, C. M. Towards subunit-specific proteasome inhibitors: synthesis and evaluation of peptide α′,β′-epoxyketones. Chem. Biol. 1999, 6, 811-822.
7. Kim, K. B.; Myung, J.; Sin, N.; Crews, C. M. Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: insights into specificity and potency. Bioorg. Med. Chem. Lett. 1999, 9, 3335-3340.
8. Britton, M.; Lucas, M. M.; Downey, S. L.; Screen, M.; Pletnev, A. A.; Verdoes, M.; Tokhunts, R. A.; Amir, O.; Goddard, A. L.; Pelphrey, P. M.; Wright, D. L.; Overkleeft, H. S.; Kisselev, A. F. Selective inhibitor of proteasome's caspase-like sites sensitizes cells to specific inhibition of chymotrypsin-like sites. Chem. Biol. 2009, 16, 1278-1289.
9. Verdoes, M.; Florea, B. I.; van der Linden, W. A.; Renou, D.; van den Nieuwendijk, A. M. C. H.; van der Marel, G. A.; Overkleeft, H. S. Mixing of peptides and electrophilic traps gives rise to potent, broad-spectrum proteasome inhibitors. Org. Biomol. Chem. 2007, 5, 1416-1426.
10. Formicola, L.; Maréchal, X.; Basse, N.; Bouvier-Durand, M.; Bonnet-Delpon, D.; Milcent, T.; Reboud-Ravaux, M.; Ongeri, S. Novel fluorinated pseudopeptides as proteasome inhibitors. Bioorg. Med. Chem. Lett. 2009, 19, 83-86.
11. (a) Berkowitz, D. B.; Karukurichi, K. R.; de la Salud-Bea, R.; Nelson, D. L.; McCune, C. D. Use of fluorinated functionality in enzyme inhibitor development: mechanistic and analytical advantages. J. Fluor. Chem. 2008, 129, 731-742.
12. (b) Molteni, M.; Pesenti, C.; Sani, M.; Volonterio, A/; Zanda, M. Fluorinated peptidomimetics: synthesis, conformational and biological features. J. Fluor. Chem. 2004, 125, 1735-1743.
13. (c)Zanda, M. Trifluoromethyl group: an effective xenobiotic function for peptide backbone modification. New. J. Chem. 2004, 28, 1401-1411.
14. For examples see: (a) Zheng, H.; Comeforo, K.; Gao, J. Expanding the fluorous arsenal: tetrafluorinated phenylalanines for protein design. J. Am. Chem. Soc. 2009, 131, 18-19.
15. (b) Holmgren, S. K.; Taylor, K. M.; Bretscher, L. E.; Raines, R. T. Code for collagen's stability deciphered. Nature 1998, 392, 666-667.
16. (c) Jäckel, C.; Salwiczek, M.; Koksch, B. Fluorine in a native protein environment-how the spatial demand and polarity of fluoroalkyl groups affect protein folding. Angew. Chem., Int. Ed. 2006, 45, 4198-4203.
17. (a) Flaherty, D. P.; Walsh, S. M.; Kiyota, T.; Dong, Y.; Ikezu, T.; Vennerstrom, J. L. Polyfluorinated bis-styrylbenzene β-amyloid plaque binding ligands. J. Med. Chem. 2007, 50, 4986-4992.
18. 19F NMR label to monitor and to control peptide aggregation in membranes. J. Am. Chem. Soc. 2008, 130, 16515-16517.
19. Verdoes, M.; Florea, B. I.; Menendez-Benito, V.; Maynard, C. J.; Witte, M. D.; van der Linden, W. A.; van den Nieuwendijk, A. M. C. H.; Hofmann, T.; Berkers, C. R.; van Leeuwen, F. W. B.; Groothuis, T. A.; Leeuwenburgh, M. A.; Ovaa, H.; Neefjes, J. J.; Filippov, D. V.; van der Marel, G. A.; Dantuma, N. P.; Overkleeft, H. S. A fluorescent broad-spectrum proteasome inhibitor for labeling proteasomes in vitro and in vivo. Chem. Biol. 2006, 13, 1217-1226. For the structure of compound 9, see SI.
20. (a) Muchamuel, T.; Basier, M.;Aujay, M. A.; Suzuki, E.; Kalim, K. W.; Lauer, C.; Sylvain, C.; Ring, E. R.; Shields, J.; Jiang, J.; Shwonek, P.; Parlati, F.; Demo, S. D.; Bennett, M. K.; Kirk, C. J.; Groettrup, M. A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat. Med. 2009, 15, 781-788.
21. (b) Demo, S. D.; Kirk, C. J.; Aujay, M. A.; Buchholz, T. J.; Dajee, M.; Ho, M. N.; Jiang, J.; Laidig, G J.; Lewis, E. R.; Parlati, F.; Shenk, K. D.; Smyth, M. S.; Sun, C. M.; Vallone, M. K.; Woo, T. M.; Molineaux, C. J.; Bennett, M. K. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007, 67, 6383-6391.
22. Van Swieten, P. F.; Leeuwenburgh, M. A.; Kessler, B. M.; Overkleeft, H. S. Bioorthogonal organic chemistry in living cells: novel strategies for labeling biomolecules. Org. Biomol. Chem. 2005, 3, 20-27.
23. Park, H. G.; Jeong, B. S.; Yoo, M. S.; Lee, J. H.; Park, M. K.; Lee, Y. J.; Kim, M. J.; Jew, S. S. Highly enantioselective and practical cinchona-derived phase-transfer catalysis for the synthesis of α-amino acids. Angew. Chem., Int. Ed. 2002, 41, 3036-3038.
24. The fluorescence intensity of the bands in Figure 3 was quantified to get an impression of the residual proteasome subunit activity. These values are shown in Table 2 in the SI.
25. Kisselev, A. F.; Garcia-Calvo, M.; Overkleeft, H. S.; Peterson, E.; Pennington, M. W.; Ploegh, H. L.; Thornberry, N. A.; Goldberg, A. L. The caspase-like sites of proteasomes, their substrate specificity, new inhibitors and substrates, and allosteric interactions with the trypsin-like sites. J. Biol. Chem. 2003, 278, 35869-35877.
26. Verdoes, M.; Hillaert, U.; Florea, B. I.; Sae-Heng, M.; Risseeuw, M. D. P.; Filippov, D. V.; van der Marel, G. A.; Overkleeft, H. S. Acetylene functionalized BODIPY dyes and their application in the synthesis of activity based proteasome probes. Bioorg. Med. Chem. Lett. 2007, 17, 6169-6171.
27. 50 values of compound 7 for each active subunit were determined in the same manner as for the other compounds: β > μM, > μM, β 0.30 μM.