Design and Stereoselective Synthesis of ProM-2: A Spirocyclic Diproline Mimetic with Polyproline Type II (PPII) Helix Conformation
Dr. Cédric Reuter
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorDr. Robert Opitz
Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)
Search for more papers by this authorDr. Arne Soicke
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorStephan Dohmen
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorMatthias Barone
Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)
Search for more papers by this authorSlim Chiha
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorMarco Tobias Klein
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorDr. Jörg-Martin Neudörfl
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorCorresponding Author
Dr. Ronald Kühne
Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)
Ronald Kühne, Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)
Hans-Günther Schmalz, Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorCorresponding Author
Prof. Dr. Hans-Günther Schmalz
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Ronald Kühne, Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)
Hans-Günther Schmalz, Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorDr. Cédric Reuter
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorDr. Robert Opitz
Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)
Search for more papers by this authorDr. Arne Soicke
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorStephan Dohmen
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorMatthias Barone
Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)
Search for more papers by this authorSlim Chiha
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorMarco Tobias Klein
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorDr. Jörg-Martin Neudörfl
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorCorresponding Author
Dr. Ronald Kühne
Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)
Ronald Kühne, Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)
Hans-Günther Schmalz, Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorCorresponding Author
Prof. Dr. Hans-Günther Schmalz
Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Ronald Kühne, Leibniz-Institut für Molekulare Pharmakologie (FMP), Campus Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin (Germany)
Hans-Günther Schmalz, Department of Chemistry, University of Cologne, Greinstrasse 4, 50939 Cologne (Germany)
Search for more papers by this authorGraphical Abstract
ProMoting proline: The spiro-tricyclic scaffold ProM-2, which is designed to be a diproline analogue locked in a polyproline type II (PPII) conformation, can be synthesized from vinylproline building blocks. ProM-2 serves as a module for the development of small molecules that specifically interfere with PPII helix-mediated protein–protein interactions (see figure).
Abstract
With the aim of developing polyproline type II helix (PPII) secondary-structure mimetics for the modulation of prolin-rich-mediated protein–protein interactions, the novel diproline mimetic ProM-2 was designed by bridging the two pyrrolidine rings of a diproline (Pro–Pro) unit through a Z-vinylidene moiety. This scaffold, which closely resembles a section of a PPII helix, was then stereoselectively synthesized by exploiting a ruthenium-catalyzed ring-closing metathesis (RCM) as a late key step. The required vinylproline building blocks, that is, (R)-N-Boc-2-vinylproline (Boc=tert-butyloxycarbonyl) and (S,S)-5-vinylproline-tert-butyl ester, were prepared on a gram scale as pure stereoisomers. The difficult peptide coupling of the sterically demanding building blocks was achieved in good yield and without epimerization by using 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU)/N,N-diisopropylethylamine (DIPEA). The RCM proceeded smoothly in the presence of the Grubbs II catalyst. Stereostructural assignments for several intermediates were secured by X-ray crystallography. As a proof of concept, it was shown that certain peptides containing ProM-2 exhibited improved (canonical) binding towards the Ena/VASP homology 1 (EVH1) domain as a relevant protein interaction target.
Supporting Information
As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.
Filename | Description |
---|---|
chem_201406493_sm_miscellaneous_information.pdf10.4 MB | miscellaneous_information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1
- 1aB. N. Bullock, A. L. Jochim, P. S. Arora, J. Am. Chem. Soc. 2011, 133, 14220–14223; for selected reviews, see:
- 1bO. Keskin, A. Gursoy, B. Ma, R. Nussinov, Chem. Rev. 2008, 108, 1225–1244;
- 1cD. González-Ruiz, H. Gohlke, Curr. Med. Chem. 2006, 13, 2607–2625;
- 1dY. Pommier, J. Cherfils, Trends Pharmacol. Sci. 2005, 26, 138–145;
- 1eA. Reayi, P. Arya, Curr. Opin. Chem. Biol. 2005, 9, 240–247;
- 1fT. Berg, Angew. Chem. Int. Ed. 2003, 42, 2462–2481;
Angew. Chem. 2003, 115, 2566–2586.
10.1002/ange.200200558 Google Scholar
- 2For selected recent reviews, see:
- 2aM. Jesus Pérez de Vega, M. Martín-Martínez, R. González-Muñiz, Curr. Top. Med. Chem. 2007, 7, 33–62;
- 2bJ. Vagner, H. Qu, V. J. Hruby, Curr. Opin. Chem. Biol. 2008, 12, 292–296;
- 2cA. Grauer, B. König, Eur. J. Org. Chem. 2009, 5099–5111;
- 2dJ. M. Mason, Future Med. Chem. 2010, 2, 1813–1822.
- 3For selected references, see:
- 3aR. E. Moellering, M. Cornejo, T. N. Davis, C. Del Bianco, J. C. Aster, S. C. Blacklow, A. L. Kung, D. G. Gilliland, G. L. Verdine, J. E. Bradner, Nature 2009, 462, 182–190;
- 3bE. Ko, J. Liu, L. M. Perez, G. Lu, A. Schaefer, K. Burgess, J. Am. Chem. Soc. 2011, 133, 462–477;
- 3cJ. H. Lee, Q. Zhang, S. Jo, S. C. Chai, M. Oh, W. Im, H. Lu, H.-S. Lim, J. Am. Chem. Soc. 2011, 133, 676–679.
- 4
- 4aL. Ball, R. Kühne, J. Schneider-Mergener, H. Oschkinat, Angew. Chem. Int. Ed. 2005, 44, 2852–2869;
Angew. Chem. 2005, 117, 2912–2930;
10.1002/ange.200400618 Google Scholar
- 4b Protein–Protein Interactions as New Drug Targets (Eds.: ), Handbook of Experimental Pharmacology, Vol. 186, Springer, Heidelberg, 2008.
- 5
- 5aL. Ball, R. Kühne, B. Hoffmann, A. Häfner, P. Schmieder, R. Volkmer-Engert, M. Hof, M. Wahl, J. Schneider-Mergener, U. Walter, H. Oschkinat, T. Jarchau, EMBO J. 2000, 19, 4903–4914;
- 5bR. Aasland, C. Abrams, C. Ampe, L. Ball, M. Bedford, G. Cesareni, M. Gimona, J. Hurley, T. Jarchau, V. Lehto, M. Lemmon, R. Linding, B. Mayer, M. Nagai, M. Sudol, U. Walter, S. Winder, FEBS Lett. 2002, 513, 141–144;
- 5cL. Ball, T. Jarchau, H. Oschkinat, U. Walter, FEBS Lett. 2002, 513, 45–52.
- 6I. Geisler, J. Chmielewski, Bioorg. Med. Chem. Lett. 2007, 17, 2765–2768.
- 7
- 7aM. Dustin, M. Olszowy, A. Holdorf, J. Bromley, N. Desai, P. Widder, F. Rosenberger, P. van der Merwe, P. Allen, A. Shaw, Cell 1998, 94, 667–677;
- 7bV. Laurent, T. Loisel, B. Harbeck, A. Wehman, L. Gröbe, B. Jockusch, J. Wehland, F. Gertler, M. Carlier, J. Cell. Biol. 1999, 144, 1245–1258.
- 8A. Goldstrohm, T. Albrecht, C. Suñé, M. Bedford, M. Garcia-Blanco, Mol. Cell. Biol. 2001, 21, 7617–7628.
- 9
- 9aB. Laggerbauer, S. Liu, E. Makarov, H.-P. Vornlocher, O. Makarova, D. Ingelfinger, T. Achsel, R. Lührmann, RNA 2005, 11, 598–608;
- 9bM. Kofler, M. Schuemann, C. Merz, D. Kosslick, A. Schlundt, A. Tannert, M. Schaefer, R. Luhrmann, E. Krause, C. Freund, Mol. Cell. Proteomics 2009, 8, 2461–2473.
- 10
- 10aC. M. Deber, F. A. Bovey, J. P. Carver, E. R. Blout, J. Am. Chem. Soc. 1970, 92, 6191–6198;
- 10bN. Helbecque, M. H. Loucheux-Lefebvre, Int. J. Peptide Protein Res. 2009, 19, 94–101;
10.1111/j.1399-3011.1982.tb03028.x Google Scholar
- 10cH. Okabayashi, T. Isemura, S. Sakakibara, Biopolymers 1968, 6, 323–330;
- 10dR. K. Dukor, T. A. Kiederling, Biopolymers 1991, 31, 1747–1761;
- 10eR. K. Dukor, T. A. Kiederling, V. Gut, Int. J. Peptide Protein Res. 2009, 38, 198–203;
10.1111/j.1399-3011.1991.tb01429.x Google Scholar
- 10fP. M. Cowan, S. McGavin, Nature 1955, 176, 501–503.
- 11R. Kühne, H. Oschkinat, C. Brockmann, H.-G. Schmalz, 2008, GER, WO 2008/040332A1.
- 12
- 12aJ. Zaminer, C. Brockmann, P. Huy, P. Opitz, C. Reuter, M. Beyermann, C. Freund, M. Müller, H. Oschkinat, R. Kühne, H.-G. Schmalz, Angew. Chem. Int. Ed. 2010, 49, 7111–7115;
Angew. Chem. 2010, 122, 7265–7269;
10.1002/ange.201001739 Google Scholar
- 12bC. Reuter, P. Huy, J.-M. Neudörfl, R. Kühne, H.-G. Schmalz, Chem. Eur. J. 2011, 17, 12037–12044;
- 12cC. Reuter, M. Kleczka, S. de Mazancourt, J.-M. Neudörfl, R. Kühne, H.-. Schmalz, Eur. J. Org. Chem. 2014, 2664–2667;
- 12dA. Soicke, C. Reuter, M. Winter, J.-M. Neudörfl, N. Schlörer, R. Kühne, H.-G. Schmalz, Eur. J. Org. Chem. 2014, 6467–6480.
- 13
- 13aM. Krause, E. W. Dent, J. E. Bear, J. J. Loureiro, F. B. Gertler, Annu. Rev. Cell Dev. Biol. 2003, 19, 541–564;
- 13bA. S. Sechi, J. Wehland, Front. Biosci. 2004, 9, 1294–1310;
- 13cF. Drees, F. B. Gertler, Curr. Opin. Neurobiol. 2008, 18, 53–59.
- 14
- 14aM. Hamon, H. Bierne, P. Cossart, Nat. Rev. Microbiol. 2006, 4, 423–434;
- 14bJ. A. Vázquez-Boland, M. Kuhn, P. Berche, T. Chakraborty, G. Domínguez-Bernal, W. Goebel, B. González-Zorn, J. Wehland, J. Kreft, Clin. Microbiol. Rev. 2001, 14, 584–640;
- 14cM. B. Goldberg, Microbiol. Mol. Biol. Rev. 2001, 65, 595–626.
- 15R. Opitz, Inhibition von Protein–Protein-Wechselwirkungen, Dissertation, FU-Berlin, 2013.
- 16Sybyl-X Molecular Modelling suite, Certara, L. P.
- 17K. E. Prehoda, D. J. Lee, W. A. Lim, Cell 1999, 97, 471–480.
- 18
- 18aT. Shono, H. Hamaguchi, Y. Matsumura, J. Am. Chem. Soc. 1975, 97, 4264–4268;
- 18bT. Shono, Tetrahedron 1984, 40, 811–850;
- 18cM. Skrinjar, L.-G. Wistrand, Tetrahedron 1991, 47, 573–582.
- 19For related transformations with 1-propenyllithium-based cuprates, see:
- 19aK. F. McClure, P. Renold, D. S. Kemp, J. Org. Chem. 1995, 60, 454–457;
- 19bE. Grovenstein Jr., K. W. Black, S. C. Goel, R. L. Hughes, J. H. Northrop, D. L. Streeter, D. VanDerveer, J. Org. Chem. 1989, 54, 1671–1679;
- 19cF. Nagaike, Y. Onuma, C. Kanazawa, H. Hojo, A. Ueki, Y. Nakahara, Y. Nakahara, Org. Lett. 2006, 8, 4465–4468.
- 20D. Rodríguez, M. Mulero, J. A. Prieto, J. Org. Chem. 2006, 71, 5826–5829.
- 21
- 21aM. E. Jung, M. A. Lyster, J. Chem. Soc. Chem. Commun. 1978, 315–316;
- 21bR. S. Lott, V. S. Chauhan, C. H. Stammer, J. Chem. Soc. Chem. Commun. 1979, 495–496;
- 21cF. Manfré, J. M. Kern, J. F. Biellmann, J. Org. Chem. 1992, 57, 2060–2065.
- 22
- 22aH. Bittermann, P. Gmeiner, J. Org. Chem. 2006, 71, 97–102;
- 22bH. Bittermann, F. Böckler, J. Einsiedel, P. Gmeiner, Chem. Eur. J. 2006, 12, 6315–6322.
- 23H. Wang, J. P. Germanas, Synlett 1999, 1, 33–36.
- 24
- 24aD. Seebach, M. Boes, R. Naef, W. B. Schweizer, J. Am. Chem. Soc. 1983, 105, 5390–5398; for a review, see:
- 24bD. Seebach, A. R. Sting, M. Hoffmann, Angew. Chem. Int. Ed. Engl. 1996, 35, 2708–2748;
Angew. Chem. 1996, 108, 2881–2921.
10.1002/ange.19961082304 Google Scholar
- 25
- 25aL. A. Carpino, J. Am. Chem. Soc. 1993, 115, 4397–4398;
- 25bL. A. Carpino, A. El-Faham, F. Albericio, Tetrahedron Lett. 1994, 35, 2279–2282; for reviews on peptide coupling, see:
- 25cA. El-Faham, F. Albericio, Chem. Rev. 2011, 111, 6557–6602;
- 25dC. A. G. N. Montalbetti, V. Falque, Tetrahedron 2005, 61, 10827–10852.
- 26G. Lesma, A. Colombo, A. Sacchetti, A. Silvani, Tetrahedron Lett. 2008, 49, 7423–7425.
- 27For reviews on microwave-assisted synthesis, see:
- 27aC. O. Kappe, Angew. Chem. Int. Ed. 2004, 43, 6250–6284;
Angew. Chem. 2004, 116, 6408–6443;
10.1002/ange.200400655 Google Scholar
- 27bA. de La Hoz, A. Diaz-Ortiz, A. Moreno, Chem. Soc. Rev. 2005, 34, 164–178;
- 27cY. Coquerel, J. Rodriguez, Eur. J. Org. Chem. 2008, 1125–1132.
- 28aP. Huy, H.-G. Schmalz, Synthesis 2011, 954–960;
- 28bP. G. M. Wuts, T. W. Greene, Greene’s Protective Groups in Organic Synthesis, 4th ed., Wiley-Interscience 2007.
- 29G. Sunilkumar, D. Nagamani, N. P. Argade, K. N. Ganesh, Synthesis 2003, 15, 2304–2306.
- 30K. Voigtritter, S. Ghorai, B. H. Lipshutz, J. Org. Chem. 2011, 76, 4697–4702.
- 31
- 31aJ. Bernstein, Polymorphism in Molecular Crystals, Clarendon, Oxford, 2002;
- 31bR. Purohit, P. Venugopalan, Resonance 2009, 14, 882–893.
- 32A. L. Spek, Acta Crystallogr. Sect. D 2009, 65, 148–155.
- 33CCDC-1042396 (Z-9), 1042403 (10), 1042402 (12), 1042397 (14, polymorph 1), 1042400 (14, polymorph 2), 1042401 (14, polymorph 3), 1042399 (18), 1042395 (19), and 1042398 (epi-19) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.
- 34
- 34aE. T. Roussos, M. Balsamo, S. K. Alford, J. B. Wyckoff, B. Gligorijevic, Y. Wang, M. Pozzuto, R. Stobezki, S. Goswami, J. E. Segall, D. A. Lauffenburger, A. R. Bresnick, F. B. Gertler, J. S. Condeelis, J. Cell Sci. 2011, 124, 2120–2131;
- 34bF. Di Modugno, M. Mottolese, L. DeMonte, P. Trono, M. Balsamo, A. Conidi, E. Melucci, I. Terrenato, F. Belleudi, M. R. Torrisi, M. Alessio, A. Santoni, P. Nisticò, PLoS ONE 2010, 5, e 15852;
- 34cA. Toyoda, H. Kawana, K. Azuhata, J. Yu, A. Omata, H. Kishi, M. Higashi, K. Harigaya, Int. J. Oncol. 2009, 34, 53–60;
- 34dS. Goswami, U. Philippar, D. Sun, A. Patsialou, J. Avraham, W. Wang, F. Di Modugno, P. Nisticò, F. B. Gertler, J. S. Condeelis, Clin. Exp. Metastasis 2009, 26, 153–159;
- 34eU. Philippar, E. T. Roussos, M. Oser, H. Yamaguchi, H.-D. Kim, S. Giampieri, Y. Wang, S. Goswami, J. B. Wyckoff, D. A. Lauffenburger, E. Sahai, J. S. Condeelis, F. B. Gertler, Development 2008, 15, 813–828.
- 35J. H. Holtzman, K. Woronowicz, D. Golemi-Kotra, A. Schepartz, Biochemistry 2007, 46, 13541–13553.
- 36P. Schanda, E. Kupce, B. Brutscher, J. Biomol. NMR 2005, 33, 199–211.