Solid-Phase Combinatorial Synthesis of Peptide-Biphenyl Hybrids as Calpain Inhibitors ²,‡ Ana Montero, §,⊥ Fernando Albericio,* ,| Miriam Royo,* ,⊥ and Bernardo Herrado ´ n* ,§ Instituto de Quı ´mica Orga ´ nica General, C.S.I.C., Juan de la CierVa 3, 28006-Madrid, Spain, and Combinatorial Chemistry Unit and Barcelona Biomedical Research Institute, Barcelona Science Park, UniVersity of Barcelona, 08028 Barcelona, Spain herradon@iqog.csic.es; mroyo@pcb.ub.es; albericio@pcb.ub.es Received September 3, 2004 ABSTRACT The combinatorial parallel synthesis of peptide-biphenyl hybrids on solid support using state of the art of peptide synthesis is reported. Key steps were the N to C addition of an amino moiety, hydrolysis of the methyl ester, and the absence of cross-linked compounds when the 2,2′-diamino-1,1′-biphenyl was incorporated. When tested for activity as calpain inhibitors, some of the compounds exhibited IC 50 values in the nanomolar range. Peptide-biphenyl hybrids A (Figure 1) are compounds in which peptides or single amino acids are bound to the 2- and 2′-positions of a biphenyl ring system. 1 Both peptides and biaryl compounds have been used as chiral catalysts, 2 as building blocks for the design of technological materials, 3 as biologically active compounds, and in other applications. 4 The combination of both structural fragments in a single molecule provides compounds with synergistic properties. 1,5 ² Taken in part from the Ph.D. Thesis of A.M. (Universidad Auto ´noma, Madrid, 2004). ‡ Abbreviations: CDI, carbonyldiimidazole; DIEA, N,N-diisopropyl- ethylamine; DIPCDI, N,N′-diisopropylcarbodiimide; DMF, N,N-dimethyl- formamide; HOAt, 1-hydroxy-7-azabenzotriazole; HOBt, 1-hydroxyben- zotriazole; MBHA, 4-methylbenzhydrylamine; PS, polystyrene; PyBOP, (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate; TEA, triethylamine; TFA, trifluoroacetic acid; THF, tetrahydrofuran. Amino acid symbols denote L-configuration. § C.S.I.C. ⊥ Combinatorial Chemistry Unit, Barcelona Science Park, University of Barcelona. | Barcelona Biomedical Research Institute, Barcelona Science Park, University of Barcelona. (1) (a) Brandmeier, V.; Feigel, M.; Bremer, M. Angew. Chem., Int. Ed. Engl. 1989, 28, 486. (b) Weigand, C.; Feigel, M.; Landgrafe, C. Chem. Commun. 1998, 679. (c) Mann, E.; Montero, A.; Maestro, M. A.; Herrado ´n, B. HelV. Chim. Acta 2002, 85, 3624. (d) Amine, M.; Atmani, Z.; El Hallaoui, A. A.; Giorgi, M.; Pierrot, M.; Re ´glier, M. Biorg. Med. Chem. Lett. 2002, 12, 57. (2) (a) Jarvo, E. R.; Miller, S. J. Tetrahedron 2002, 58, 2481. (b) McCarthy, M.; Guiry, P. J. Tetrahedron 2001, 57, 3809. (3) (a) Voyer, N. Top. Curr. Chem. 1997, 184, 1. (b) Hartley, C. S.; Lazar, C.; Wand, M. D.; Lemieux, R. P. J. Am. Chem. Soc. 2002, 124, 13513. (4) (a) Hajduk, P. J.; Bures, M.; Praestgaard, J.; Fesik, S. W. J. Med. Chem. 2000, 43, 3443. (b) Kutzki, O.; Park, H. S.; Ernst, J. T.; Orner, B. P.; Yin, H.; Hamilton, A. D. J. Am. Chem. Soc., 2002, 124, 11838. (c) Wang, W.; Cai, M.; Xiong, C.; Zhang, J.; Trivedi, D.; Hruby, V. J. Tetrahedron 2002, 58, 7365. (d) Peukert, S.; Brendel, J.; Pirard, B.; Bru ¨ggemann, A.; Below, P.; Kleemann, H.-W.; Hemmerle, H.; Schmidt, W. J. Med. Chem. 2003, 46, 486. (e) Sheppard, G. S.; Kawai, M.; Craig, R. A.; Davidson, D. J.; Majest, S. M.; Bell, R. L.; Henkin, J. Biorg. Med. Chem. Lett. 2004, 14, 865. Figure 1. Generic structure of peptide-biphenyl hybrid A. ORGANIC LETTERS 2004 Vol. 6, No. 22 4089-4092 10.1021/ol048216j CCC: $27.50 © 2004 American Chemical Society Published on Web 09/29/2004