Synlett 2015; 26(04): 426-431
DOI: 10.1055/s-0034-1379947
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© Georg Thieme Verlag Stuttgart · New York

The Frequent Application of Multicomponent and Cycloaddition Reactions for the Synthesis of Potent MDM2-p53 Inhibitors

Andreas Gollner*
Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer Gasse 5–11, 1121 Vienna, Austria   Email: andreas.gollner@boehringer-ingelheim.com
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Further Information

Publication History

Received: 14 November 2014

Accepted: 03 December 2014

Publication Date:
19 January 2015 (online)


Dedicated to Professor Johann Mulzer on occasion of his 70th birthday

Abstract

Multicomponent reactions (MCRs) and cycloaddition reactions can generate structurally complex molecules in a very efficient manner and are a valuable tool not only for the synthesis of compound libraries for screening campaigns, but also for the optimization of compounds during lead optimization. This article highlights the frequent application of these reactions for the synthesis of potent inhibitors of the MDM2-p53 protein–protein interaction.

 
  • References and Notes

  • 1 Wells JA, McClendon CL. Nature (London) 2007; 450: 1001
  • 2 Surade S, Blundell TL. Chem. Biol. 2012; 19: 42
  • 3 Sperandio O, Reynes CH, Camproux A.-C, Villoutreix BO. Drug Discovery Today 2010; 15: 220
  • 4 Morelli X, Bourgeas R, Roche P. Curr. Opin. Chem. Biol. 2011; 15: 475
  • 5 Villoutreix BO, Labbe C, Lagorce D, Laconde G, Sperandio O. Curr Pharm Des. 2012; 18: 4648
  • 6 Khoury K, Popowicz GM, Holak TA, Dömling A. Med. Chem. Commun. 2011; 2: 246
  • 7 Levine AJ. Cell 1997; 88: 323
  • 8 Bond GL, Hu W, Levine AJ. Curr. Cancer Drug Targets 2005; 5: 3
  • 9 Vassilev LT. Trends Mol. Med. 2007; 13: 23
  • 10 Dömling A, Ugi I. Angew. Chem. Int. Ed. 2000; 39: 3168
  • 11 Dömling A, Wang W, Wang K. Chem. Rev. 2012; 112: 3083
  • 12 Dömling A, Zarganes-Tzitzikas T. Org. Chem. Front. 2014; 1: 834
  • 13 Wirth M, Sauer WH. B. Mol. Inform. 2011; 30: 677
  • 14 Roughley SD, Jordan AM. J. Med. Chem. 2011; 54: 3451
  • 15 This constitutes the compound series with reported example compounds that show IC50s or KDs of below 100 nM in a biochemical or biophysical MDM2 binding assay.
  • 16 Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Ding Y, Gao W, Stuckey J, Krajewski K, Roller PP, Tomita Y, Parrish DA, Deschamps JR, Wang S. J. Am. Chem. Soc. 2005; 127: 10130
  • 17 Wang S, Ding K, Lu Y, Nikolovska-Coleska Z, Qiu S, Wang G, Qin D, Shangary S. Int. Patent Appl. WO2006091646A2, 2006
  • 18 Wang S, Qin D, Chen J, Yu S. Int. Patent Appl. WO2008036168A2, 2008
  • 19 Wang S, Yu S, Sun W, Shangary SK, Sun D, Zou P, Zhao Y, Mceachern D. Int. Patent Appl. WO2011060049A2, 2011
  • 20 Wang S, Zhao Y, Sun W, Kumar S, Leopold L, Debussche L, Barriere C, Carry J.-C, Amaning K. Int Patent Appl. WO2012065022A2, 2012
  • 21 Wang S, Sun W, Aguilar A, Garcia-Echeverria C. Int Patent Appl. WO2012155066A2, 2012
  • 22 Sugimoto Y, Uoto K, Miyazaki M, Setoguchi M, Taniguchi T, Yoshida K, Yamaguchi A, Yoshida S, Wakabayashi T. Int. Patent Appl. WO2012121361A1, 2012
  • 23 Yoshida S, Sugimoto Y. Int. Patent Appl. WO2014038606A1, 2014
  • 24 Chu X.-J, Ding Q, Zhang J, Zhang Z. Int. Patent Appl. WO2011134925A1, 2011
  • 25 Artkovitz DJ, Chu X.-J, Ding Q, Karanchi PS, Liu J.-J, So S.-S, Zhang J, Zhang Z. Int. Patent Appl. WO2012022707A1, 2012
  • 26 Zhang Z, Ding Q, Liu J.-J, Zhang J, Jiang N, Chu X.-J, Bartkovitz D, Luk K.-C, Janson C, Tovar C, Filipovic ZM, Higgins B, Glenn K, Packmann K, Vassiliev LT, Graves B. Bioorg. Med. Chem. 2014; 22: 4001
  • 27 Ding Q, Zhang Z, Liu J.-J, Jiang N, Zhang J, Ross TM, Chu X.-J, Bartkovitz D, Podlaski F, Janson C, Tovar C, Filipovic ZM, Higgins B, Glenn K, Packman K, Vassiliev LT, Graves B. J. Med. Chem. 2013; 56: 5979
  • 28 Chen L, Han X, He Y, Yang S, Zhang Z. Int. Patent Appl. WO2009080488A1, 2009
  • 29 Burdack C, Kalinski C, Ross G, Weber L, Khazak V. Int. Patent Appl. WO2010028862A1, 2010
  • 30 Furet P, Kallen J, Lorber J, Masuya K. Int. Patent Appl. WO2012176123A1, 2012
  • 31 Sebahar PR, Williams RM. J. Am. Chem. Soc. 2000; 122: 5666
  • 32 Zhao Y, Liu L, Sun W, Lu J, McEachern D, Li X, Shanghai Y, Bernard D, Ochsenbein P, Ferey V, Carry J.-C, Deschamps JR, Sun D, Wang S. J. Am. Chem. Soc. 2013; 135: 7223
  • 33 Wang S, Sun W, Zhao Y, McEachern D, Meaux I, Barriere C, Stuckey JA, Meagher JL, Bai L, Liu L, Hoffman-Luca CG, Lu J, Shangary S, Yu S, Bernard D, Aguilar A, Dos-Santos O, Besret L, Guerif S, Pannier P, Gorge-Bernat D, Debussche L. Cancer Res. 2014; 74: 5855
  • 34 Zhang Z, Ding Q, Liu J.-J, Zhang J, Jiang N, Chu X.-J, Bartkovitz D, Luk K.-C, Janson C, Tovar C, Filipovic ZM, Higgins B, Glenn K, Packmann K, Vassiliev LT, Graves B. Bioorg. Med. Chem. 2014; 22: 4001
  • 35 Shu L, Li Z, Gu C, Fishlock D. Org. Process Res. Dev. 2013; 17: 247
  • 36 Wei J, Shaw JT. Org. Lett. 2007; 9: 4077
  • 37 Van Leusen AM, Wildeman J, Oldenziel OH. J. Org. Chem. 1977; 42: 1153
  • 38 Gokel G, Lüdke G, Ugi I In Isonitrile Chemistry . Ugi I. Academic; New York: 1971: 145
  • 39 Parks DJ, LaFrance LV, Calvo RR, Milkiewicz KL, Gupta V, Lattanze J, Ramachandren K, Caver TE, Petrella EC, Cummings MD, Maguire D, Grasberger BL, Lu T. Bioorg. Med. Chem. Lett. 2005; 15: 765
  • 40 Carey JS, Laffan D, Thomson C, Williams MT. Org. Biomol. Chem. 2006; 4: 2337
  • 41 Walters WP, Green J, Weiss JR, Murcko MA. J. Med. Chem. 2011; 54: 6405