ACS Combinatorial Science
RESEARCH ARTICLE
’ ACKNOWLEDGMENT
(18) Rodriguez, J. M.; Hamilton, A. D. Benzoylurea Oligomers:
Synthetic Foldamers That Mimic Extended R Helices. Angew. Chem., Int.
Ed. 2007, 46, 8614–8617.
(19) Rodriguez, J. M.; Ross, N. T.; Katt, W. P.; Dhar, D.; Lee, G. I.;
Hamilton, A. D. Structure and Function of Benzoylurea-Derived R-Helix
Mimetics Targeting the Bcl-xL/Bak Binding Interface. ChemMedChem
2009, 4, 649–656.
The authors are grateful to H. Passgang, A. Reiner, M.
Schneider, S. Terhart-Krabbe, and I. Kretschmer for assistance.
This work has been supported by the German Research Founda-
tion (GRK 804).
(20) Xiao, X.; Ngu, K.; Chao, C.; Patel, D. V. Selective Solid Phase
Synthesis of Ureas and Hydantoins from Common Phenyl Carbamate
Intermediates. J. Org. Chem. 1997, 62, 6968–6973.
(21) Matthews, J.; Rivero, R. A. Base-Promoted Solid-Phase Synthe-
sis of Substituted Hydantoins and Thiohydantoins. J. Org. Chem. 1997,
62, 6090–6092.
(22) Chong, P. Y.; Petillo, P. A. Solid Phase Urea Synthesis: An
Efficient and Direct Conversion of Fmoc-Protected Amines to Ureas.
Tetrahedron Lett. 1999, 40, 4501–4504.
(23) Hamuro, Y.; Marshall, W. J.; Scialdone, M. A. Solid-Phase
Synthesis of Acyclic and Cyclic Amino Acid Derived Urea Peptidomi-
metics Using Phoxime Resin. J. Comb. Chem. 1999, 1, 163–172.
(24) Migawa, M. T.; Swayze, E. E. A Solid-Phase Synthesis of N,-
N0-Disubstituted Ureas and Perhydroimidazo[1,5-a]pyrazines via the
Curtius Rearrangement. Org. Lett. 2000, 2, 3309–3311.
(25) Nefzi, A.; Ong, N. A.; Houghten, R. A. An Efficient Two-Step
Synthesis of Mono-, Di- and Triureas from Resin-Bound Amides.
Tetrahedron Lett. 2000, 41, 5441–5446.
(26) Br€ase, S.; Dahmen, S.; Pfefferkorn, M. Solid-Phase Synthesis of
Urea and Amide Libraries Using the T2 Triazene Linker. J. Comb. Chem.
2000, 2, 710–715.
(27) Acharya, A. N.; Nefzi, A.; Ostresh, J. M.; Houghten, R. A.
Tethered Libraries: Solid-Phase Synthesis of Substituted Urea-Linked
Bicyclic Guanidines. J. Comb. Chem. 2001, 3, 189–195.
’ REFERENCES
(1) Smith, M. C.; Riskin, B. J. The Clinical Use of Barbiturates in
Neurological Disorders. Drugs 1991, 42, 365–378.
(2) Nefzi, A.; Giulianotti, M.; Truong, L.; Rattan, S.; Ostresh, J. M.;
Houghten, R. A. Solid-Phase Synthesis of Linear Ureas Tethered to
Hydantoins and Thiohydantoins. J. Comb. Chem. 2002, 4, 175–178.
(3) Meusel, M.; Ambrozak, A.; Hecker, T. K.; G€utschow, M. The
Aminobarbituric Acid-Hydantoin Rearrangement. J. Org. Chem. 2003,
68, 4684–4692.
(4) Meusel, M.; G€utschow, M. Recent Developments in Hydantoin
Chemistry. A Review. Org. Prep. Proc. Int. 2004, 36, 391–443.
(5) Bialer, M. New Antiepileptic Drugs That are Second Generation
to Existing Antiepileptic Drugs. Expert Opin. Invest. Drugs 2006, 15,
637–647.
(6) Bialer, M.; Yagen, B. Valproic Acid: Second Generation.
Neurotherapeutics 2007, 4, 130–137.
(7) Pessah, N.; Bialer, M.; Wlodarczyk, B.; Finnell, R. H.; Yagen, B.
R-Fluoro-2,2,3,3-Tetramethylcyclopropanecarboxamide, A Novel Potent
Anticonvulsant Derivative of a Cyclic Analogue of Valproic Acid.
J. Med. Chem. 2009, 52, 2233–2242.
(8) Bialer, M.; White, H. S. Key Factors in the Discovery and
Development of New Antiepileptic Drugs. Nat. Rev. Drug Discovery
2010, 9, 68–82.
(9) Sobol, E.; Bialer, M.; Yagen, B. Tetramethylcyclopropyl Ana-
logue of a Leading Antiepileptic Drug, Valproic Acid. Synthesis and
Evaluation of Anticonvulsant Activity of Its Amide Derivatives. J. Med.
Chem. 2004, 47, 4316–4326.
(10) Shimshoni, J. A.; Yagen, B.; Pessah, N.; Wlodarczyk, B.; Finnell,
R. H.; Bialer, M. Anticonvulsant Profile and Teratogenicity of 3,-
3-Dimethylbutanoylurea: A Potential For a Second Generation Drug
to Valproic Acid. Epilepsia 2008, 49, 1202–1212.
(11) Librowski, T.; Kubacka, M.; Meusel, M.; Scolari, S.; M€uller, C. E.;
G€utschow, M. Evaluation of Anticonvulsant and Analgesic Effects of Benzyl-
and Benzhydryl Ureides. Eur. J. Pharmacol. 2007, 559, 138–149.
(12) Klabunde, T.; Wendt, K. U.; Kadereit, D.; Brachvogel, V.;
Burger, H. J.; Herling, A. W.; Oikonomakos, N. G.; Kosmopoulou,
M. N.; Schmoll, D.; Sarubbi, E.; von Roedern, E.; Sch€onafinger, K.;
Defossa, E. Acyl Ureas as Human Liver Glycogen Phosphorylase
Inhibitors for the Treatment of Type 2 Diabetes. J. Med. Chem. 2005,
48, 6178–6193.
(28) Meusel, M.; G€utschow, M. Preparation of a Novel Polystyrene-
Based Urea Resin. Tetrahedron Lett. 2005, 46, 2231–2233.
(29) Lee, S.-H.; Matsushita, H.; Koch, G.; Zimmermann, J.; Clapham,
B.; Janda, K. D. Smart Cleavage Reactions: the Synthesis of an Array
of Ureas from Polymer-Bound Carbamates. J. Comb. Chem. 2004, 6,
822–827.
(30) Boeijen, A.; Kruijtzer, J. A. W.; Liskamp, R. M. J. Combinatorial
Chemistry of Hydantoins. Bioorg. Med. Chem. Lett. 1998, 8, 2375–2380.
(31) Wu, S.; Janusz, J. M. Solid-Phase Synthesis of 3-Aminohydan-
toin, Dihydrouracil, Thiohydantoin and Dihydrothiouracil Derivatives.
Tetrahedron Lett. 2000, 41, 1165–1169.
(32) Blanco-Canosa, J.; Dawson, P. An Efficient Fmoc-SPPS Ap-
proach for the Generation of Thioester Peptide Precursors for Use in
Native Chemical Ligation. Angew. Chem., Int. Ed. 2008, 47, 6851–6855.
(33) Ravn, J.; Ankersen, M.; Begtrup, M.; Lau, J. F. A Novel Solid-
Phase Synthesis of Di- and Trisubstituted N-Acyl Ureas. Tetrahedron
Lett. 2003, 44, 6931–6935.
(13) Oikonomakos, N. G.; Kosmopoulou, M. N.; Chrysina, E. D.;
Leonidas, D. D.; Kostas, I. D.; Wendt, K. U.; Klabunde, T.; Defossa, E.
Crystallographic Studies on Acyl Ureas, A New Class of Glycogen
Phosphorylase Inhibitors, as Potential Antidiabetic Drugs. Protein Sci.
2005, 14, 1760–1771.
(14) Li, J.-N.; Song, D.-Q.; Lin, Y.-H.; Hu, Q.-Y.; Yin, L.; Bekesi, G.;
Holland, J. F.; Jiang, J.-D. Inhibition of Microtubule Polymerization by
3-Bromopropionylamino Benzoylurea (JIMB01), A New Cancericidal
Tubulin Ligand. Biochem. Pharmacol. 2003, 65, 1691–1699.
(15) Song, D.-Q.; Wang, Y.-M.; Du, N.-N.; He, W.-Y.; Chen, K.-L.;
Wang, G.-F.; Yang, P.; Wu, L.-Z.; Zhang, X.-B.; Jiang, J.-D. Synthesis and
Activity Evaluation of Benzoylurea Derivatives as Potential Antiprolif-
erative Agents. Bioorg. Med. Chem. Lett. 2009, 19, 755–758.
(16) Okada, H.; Kato, M.; Koyanagi, T.; Mizuno, K. Synthesis and
Antitumor Activities of Water-Soluble Benzoylphenylureas. Chem.
Pharm. Bull. 1999, 47, 430–433.
(34) Brown, E. G.; Nuss, J. M. Alkylation of Rink's Amide Linker on
Polystyrene Resin: A Reductive Amination Approach to Modified
Amine-Linkers for the Solid Phase Synthesis of N-Substituted Amide
Derivatives. Tetrahedron Lett. 1997, 38, 8457–8460.
(35) Kutschy, P.; Dzurilla, M.; Ficeri, V.; Koꢀsꢀcík, D. New Synthesis
of N-Acylurea Derivatives. Collect. Czech. Chem. Commun. 1993, 58,
575–587.
(36) Frezza, M.; Castang, S.; Estephane, J.; Soulꢁere, L.; Deshayes, C.;
Chantegrel, B.; Nasser, W.; Queneau, Y.; Reverchon, S; Doutheau, A.
Synthesis and Biological Evaluation of Homoserine Lactone Derived
Ureas as Antagonists of Bacterial Quorum Sensing. Bioorg. Med. Chem.
2006, 14, 4781–4791.
(37) Ranise, A.; Schenone, S.; Bruno, O.; Bondavalli, F.; Filippelli,
W.; Falcone, G.; Rivaldi, B. N-Acyl-N-phenyl Ureas of Piperidine and
Substituted Piperidines Endowed with Anti-Inflammatory and Anti-
Proliferative Activities. Farmaco 2001, 56, 647–657.
(17) Lessene, G.; Smith, B. J.; Gable, R. W.; Baell, J. B. Characteriza-
tion of the Two Fundamental Conformations of Benzoylureas and
Elucidation of the Factors That Facilitate Their Conformational Inter-
change. J. Org. Chem. 2009, 74, 6511–6525.
(38) Balzarini, J.; Baumgartner, H.; Bodenteich, M.; De Clercq, E.;
Griengl, H. Synthesis and Antiviral Activity of the Enantiomeric Forms
of Carba-5-iodo-20-deoxyuridine and Carba-(E)-5-(2-bromovinyl)-
20-deoxyuridine. J. Med. Chem. 1989, 32, 1861–1865.
63
dx.doi.org/10.1021/co100020b |ACS Comb. Sci. 2011, 13, 59–64