Synthesis 2016; 48(10): 1457-1473
DOI: 10.1055/s-0035-1561414
short review
© Georg Thieme Verlag Stuttgart · New York

Diversity-Oriented Synthesis of Macrocycle Libraries for Drug Discovery and Chemical Biology

Súil Collins
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK   Email: [email protected]
,
Sean Bartlett
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK   Email: [email protected]
,
Feilin Nie
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK   Email: [email protected]
,
Hannah F. Sore
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK   Email: [email protected]
,
David R. Spring*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 23 December 2015

Accepted after revision: 15 February 2016

Publication Date:
17 March 2016 (online)


Abstract

The identification of new bioactive small molecules is increasingly reliant upon the synthesis and screening of chemical libraries. The extent of structural diversity and the proportion of unique scaffolds in a library are commonly acknowledged to be the most important factors in determining its success in identifying new biologically relevant compounds. Particularly important in this respect are macrocycles, which display unique physicochemical attributes and are used in many clinical applications. Despite these advantages, macrocycles remain under-represented in many contemporary screening collections, predominantly due to their synthetic intractability. Diversity-oriented­ synthesis is a powerful method for the construction of deliberately diverse collections of small molecules, and many research groups are working to apply its principles to the synthesis of structurally and functionally diverse macrocyclic libraries. In this short review we introduce why macrocycles are promising chemotypes in screening libraries, especially for challenging biological targets such as protein–protein interactions, and we review a collection of strategies developed in our laboratory for the diversity-oriented synthesis of macrocycle libraries. We analyse a selection of the macrocycle collections generated using these approaches and conclude with our perspective on future directions of the field.

1 Introduction

1.1 Chemical Libraries in Drug Discovery and Chemical Biology

1.2 Macrocycles in Screening Collections

1.3 Diversity-Oriented Synthesis

2 Build/Couple/Pair

2.1 Strategy Overview

2.2 Typical B/C/P Strategies

2.3 Advanced B/C/P Strategies

2.4 Two-Directional Synthesis

3 Alternative Approaches to Macrocycle Library Synthesis

4 Discussion and Concluding Remarks

 
  • References

  • 1 O’Connor CJ, Laraia L, Spring DR. Chem. Soc. Rev. 2011; 40: 4332
  • 2 Dobson CM. Nature 2004; 432: 824
  • 3 Arrowsmith CH, Audia JE, Austin C, Baell J, Bennett J, Blagg J, Bountra C, Brennan PE, Brown PJ, Bunnage ME, Buser-Doepner C, Campbell RM, Carter AJ, Cohen P, Copeland RA, Cravatt B, Dahlin JL, Dhanak D, Edwards AM, Frye SV, Gray N, Grimshaw CE, Hepworth D, Howe T, Huber KV. M, Jin J, Knapp S, Kotz JD, Kruger RG, Lowe D, Mader MM, Marsden B, Mueller-Fahrnow A, Müller S, O’Hagan RC, Overington JP, Owen DR, Rosenberg SH, Roth B, Ross R, Schapira M, Schreiber SL, Shoichet B, Sundström M, Superti-Furga G, Taunton J, Toledo-Sherman L, Walpole C, Walters MA, Willson TM, Workman P, Young RN, Zuercher WJ. Nat. Chem. Biol. 2015; 11: 536
  • 4 Nielsen TE, Schreiber SL. Angew. Chem. Int. Ed. 2008; 47: 48
  • 5 Shelat AA, Guy RK. Nat. Chem. Biol. 2007; 3: 442
  • 6 Galloway WR. J. D, Isidro-Llobet A, Spring DR. Nat. Commun. 2010; 1: 1
  • 7 O’Connor CJ, Beckmann HS. G, Spring DR. Chem. Soc. Rev. 2012; 41: 4444
  • 8 Galloway WR, Spring DR. Expert Opin. Drug Discov. 2009; 4: 467
  • 9 Ziegler S, Pries V, Hedberg C, Waldmann H. Angew. Chem. Int. Ed. 2013; 52: 2744
  • 10 Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Nat. Rev. Drug Discov. 2007; 6: 29
  • 11 Franc I, Lipinski A, Feeney PJ. Adv. Drug Delivery Rev. 1997; 23: 3
  • 12 Doak BC, Over B, Giordanetto F, Kihlberg J. Chem. Biol. 2014; 21: 1115
  • 13 Zhang M.-Q, Wilkinson B. Curr. Opin. Biotechnol. 2007; 18: 478
  • 14 Feher M, Schmidt JM. J. Chem. Inf. Comput. Sci. 2003; 43: 218
  • 15 Lipinski C, Hopkins A. Nature 2004; 432: 855
  • 16 Hopkins AL, Mason JS, Overington JP. Curr. Opin. Struct. Biol. 2006; 16: 127
  • 17 Symposium-in-Print: Bioorg. Med. Chem. 2015; 23: 2607
  • 18 Marsault E, Peterson ML. J. Med. Chem. 2011; 54: 1961
  • 19 Driggers EM, Hale SP, Lee J, Terrett NK. Nat. Rev. Drug Discov. 2008; 7: 608
  • 20 Wessjohann LA, Ruijter E, Garcia-Rivera D, Brandt W. Mol. Divers. 2005; 9: 171
  • 21 Martí-Centelles V, Pandey MD, Burguete MI, Luis SV. Chem. Rev. 2015; 115: 8736
  • 22 Villar EA, Beglov D, Chennamadhavuni S, Porco JA, Kozakov D, Vajda S, Whitty A. Nat. Chem. Biol. 2014; 10: 723
  • 23 Yu X, Sun D. Molecules 2013; 18: 6230
  • 24 Swinney DC, Anthony J. Nat. Rev. Drug Discov. 2011; 10: 507
  • 25 Xie J, Bogliotti N. Chem. Rev. 2014; 114: 7678
  • 26 Giordanetto F, Kihlberg J. J. Med. Chem. 2014; 57: 278
  • 27 Madsen CM, Clausen MH. Eur. J. Org. Chem. 2011; 3107
  • 28 Bade R, Chan H.-F, Reynisson J. Eur. J. Med. Chem. 2010; 45: 5646
  • 29 Mallinson J, Collins I. Future Med. Chem. 2012; 4: 1409
  • 30 Strausberg RL, Schreiber SL. Science 2003; 300: 294
  • 31 Thomas GL, Wyatt EE, Spring DR. Curr. Opin. Drug Discov. Dev. 2006; 9: 700
  • 32 Spandl RJ, Bender A, Spring DR. Org. Biomol. Chem. 2008; 6: 1149
  • 33 Schreiber SL. Science 2000; 287: 1964
  • 34 Sauer WH. B, Schwarz MK. J. Chem. Inf. Comput. Sci. 2003; 43: 987
  • 35 Clemons PA, Bodycombe NE, Carrinski HA, Wilson JA, Shamji AF, Wagner BK, Koehler AN, Schreiber SL. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 18787
  • 36 Nielsen TE, Schreiber SL. Angew. Chem. Int. Ed. 2007; 47: 48
  • 37 Uchida T, Rodriquez M, Schreiber SL. Org. Lett. 2009; 11: 1559
  • 38 Isidro-Llobet A, Murillo T, Bello P, Cilibrizzi A, Hodgkinson JT, Galloway WR. J. D, Bender A, Welch M, Spring DR. Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 6793
  • 39 Comer E, Liu H, Joliton A, Clabaut A, Johnson C, Akella LB, Marcaurelle LA. Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 6751
  • 40 Pizzirani D, Kaya T, Clemons PA, Schreiber SL. Org. Lett. 2010; 12: 2822
  • 41 Fitzgerald ME, Mulrooney CA, Duvall JR, Wei J, Suh BC, Akella LB, Vrcic A, Marcaurelle LA. ACS Comb. Sci. 2012; 14: 89
  • 42 Beckmann HS. G, Nie F, Hagerman CE, Johansson H, Tan YS, Wilcke D, Spring DR. Nat. Chem. 2013; 5: 861
  • 43 Rezai T, Bock JE, Zhou MV, Kalyanaraman C, Lokey RS, Jacobson MP. J. Am. Chem. Soc. 2006; 128: 14073
  • 44 Hewitt WM, Leung SS. F, Pye CR, Ponkey AR, Bednarek M, Jacobson MP, Lokey RS. J. Am. Chem. Soc. 2015; 137: 715
  • 45 Vagner J, Qu H, Hruby VJ. Curr. Opin. Chem. Biol. 2008; 12: 292
  • 46 Yoo B, Shin SB. Y, Huang ML, Kirshenbaum K. Chem. Eur. J. 2010; 16: 5527
  • 47 Xu Z, Wheeler KA, Baures PW. Molecules 2012; 17: 5346
  • 48 Bock VD, Speijer D, Hiemstra H, van Maarseveen JH. Org. Biomol. Chem. 2007; 5: 971
  • 49 Borthwick A. Chem. Rev. 2012; 112: 3641
  • 50 Cornacchia C, Cacciatore I, Baldassarre L, Mollica A, Feliciani F, Pinnen F. Mini Rev. Med. Chem. 2012; 12: 2
  • 51 Huang R.-M, Yi X.-X, Zhou Y, Su X, Peng Y, Gao C.-H. Mar. Drugs 2014; 12: 6213
  • 52 Ciardiello JJ, Galloway WR. J. D, O’Connor CJ, Sore HF, Stokes JE, Wu Y, Spring DR. Tetrahedron 2015; in press; DOI: 10.1016/j.tet.2015.10.061
  • 53 Maurya SK, Dow M, Warriner S, Nelson A. Beilstein J. Org. Chem. 2013; 9: 775
  • 54 Isidro-Llobet A, Hadje Georgiou K, Galloway WR. J. D, Giacomini E, Hansen MR, Méndez-Abt G, Tan YS, Carro L, Sore H, Spring DR. Org. Biomol. Chem. 2015; 13: 4570
  • 55 O’Connell KM. G, Beckmann HS. G, Laraia L, Horsley HT, Bender A, Venkitaraman AR, Spring DR. Org. Biomol. Chem. 2012; 10: 7545
  • 56 MacMillan DW. C. Nature 2008; 455: 304
  • 57 Hopkinson MN, Richter C, Schedler M, Glorius F. Nature 2014; 510: 485
  • 58 Enders D, Niemeier O, Henseler A. Chem. Rev. 2007; 107: 5606
  • 59 Grossmann A, Bartlett S, Janecek M, Hodgkinson JT, Spring DR. Angew. Chem. 2014; 126: 13309
  • 60 Luo T, Schreiber SL. J. Am. Chem. Soc. 2009; 131: 5667
  • 61 Marcaurelle LA, Comer E, Dandapani S, Duvall JR, Gerard B, Kesavan S, Lee MD, Liu H, Lowe JT, Marie J.-C, Mulrooney CA, Pandya BA, Rowley A, Ryba TD, Palmer M, Foley MA. J. Am. Chem. Soc. 2010; 132: 16962
  • 62 Kopp F, Stratton CF, Akella LB, Tan DS. Nat. Chem. Biol. 2012; 8: 358
  • 63 Krieger J.-P, Ricci G, Lesuisse D, Meyer C, Cossy J. Angew. Chem. Int. Ed. 2014; 53: 8705
  • 64 Kitsiou C, Hindes JJ, I’Anson P, Jackson P, Wilson TC, Daly EK, Felstead HR, Hearnshaw P, Unsworth WP. Angew. Chem. Int. Ed. 2015; 54: 15794
  • 65 Wetzel S, Bon RS, Kumar K, Waldmann H. Angew. Chem. Int. Ed. 2011; 50: 10800
  • 66 Nadin A, Hattotuwagama C, Churcher I. Angew. Chem. Int. Ed. 2012; 51: 1114
  • 67 Karageorgis G, Warriner S, Nelson A. Nat. Chem. 2014; 6: 872
  • 68 Seigal BA, Connors WH, Fraley A, Borzilleri RM, Carter PH, Emanuel SL, Fargnoli J, Kim K, Lei M, Naglich JG, Pokross ME, Posy SL, Shen H, Surti N, Talbott R, Zhang Y, Terrett NK. J. Med. Chem. 2015; 58: 2855
  • 69 Smith JM, Frost JR, Fasan R. J. Org. Chem. 2013; 78: 3525
  • 70 Asai T, Tsukada K, Ise S, Shirata N, Hashimoto M, Fujii I, Gomi K, Nakagawara K, Kodama EN, Oshima Y. Nat. Chem. 2015; 7: 737
  • 71 Kohli RM, Burke MD, Tao J, Walsh CT. J. Am. Chem. Soc. 2003; 125: 7160
  • 72 Scheuermann J, Neri D. Curr. Opin. Chem. Biol. 2015; 26: 99
  • 73 Koutsoukas A, Paricharak S, Galloway WR. J. D, Spring DR, IJzerman AP, Glen RC, Marcus D, Bender A. J. Chem. Inf. Model. 2014; 54: 230
  • 74 Bender A, Glen RC. Org. Biomol. Chem. 2004; 2: 3204
  • 75 Jorgensen WL. Science 2004; 303: 1813
  • 76 Allen SE, Dokholyan NV, Bowers AA. ACS Chem. Biol. 2016; 11: 10
  • 77 Sliwoski G, Kothiwale S, Meiler J, Lowe E. Pharmacol. Rev. 2014; 66: 334
  • 78 Yudin AK. Chem. Sci. 2015; 6: 30
  • 79 Huggins DJ, Venkitaraman AR, Spring DR. ACS Chem. Biol. 2011; 6: 208
  • 80 Bauer RA, Wurst JM, Tan DS. Curr. Opin. Chem. Biol. 2010; 14: 308
  • 81 Editorial: Nat. Chem. Biol. 2007; 3: 433
  • 82 Stein RL. J. Biomol. Screening 2003; 8: 615
  • 83 Mullard A. Nat. Rev. Drug Discov. 2013; 12: 173
  • 84 Austin CP, Brady LS, Insel TR, Collins FS. Science 2004; 306: 1138
  • 85 Ibbeson BM, Laraia L, Alza E, O’Connor CJ, Tan YS, Davies HM. L, McKenzie G, Venkitaraman AR, Spring DR. Nat. Commun. 2014; 5: 3155
  • 86 Thomas GL, Spandl RJ, Glansdorp FG, Welch M, Bender A, Cockfield J, Lindsay JA, Bryant C, Brown DF. J, Loiseleur O, Rudyk H, Ladlow M, Spring DR. Angew. Chem. Int. Ed. 2008; 47: 2808
  • 87 Robinson A, Thomas GL, Spandl RJ, Welch M, Spring DR. Org. Biomol. Chem. 2008; 6: 2978
  • 88 Stanton BZ, Peng LF, Maloof N, Nakai K, Wang X, Duffner JL, Taveras KM, Hyman JM, Lee SW, Koehler AN, Chen JK, Fox JL, Mandinova A, Schreiber SL. Nat. Chem. Biol. 2009; 5: 154
  • 89 Peng LF, Stanton BZ, Maloof N, Wang X, Schreiber SL. Bioorg. Med. Chem. Lett. 2009; 19: 6319
  • 90 Comer E, Beaudoin JA, Kato N, Fitzgerald ME, Heidebrecht RW, duPont Lee M, Masi D, Mercier M, Mulrooney C, Muncipinto G, Rowley A, Crespo-Llado K, Serrano AE, Lukens AK, Wiegand RC, Wirth DF, Palmer MA, Foley MA, Munoz B, Scherer CA, Duvall JR, Schreiber SL. J. Med. Chem. 2014; 57: 8496
  • 91 Heidebrecht RW, Mulrooney C, Austin CP, Barker RH, Beaudoin JA, Cheng KC, Comer E, Dandapani S, Dick J, Duvall JR, Ekland EH, Fidock DA, Fitzgerald ME, Foley M, Guha R, Hinkson P, Kramer M, Lukens AK, Masi D, Marcaurelle LA, Su X, Thomas CJ, We M, Wiegand RC, Wirth D, Xia M, Yuan J, Zhao J, Palmer M, Munoz B, Schreiber S. ACS Med. Chem. Lett. 2012; 3: 112
  • 92 Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, Schacht AL. Nat. Rev. Drug Discov. 2010; 9: 203
  • 93 Garcia-Castro M, Kremer L, Reinkemeier CD, Unkelbach C, Strohmann C, Ziegler S, Ostermann C, Kumar K. Nat. Commun. 2015; 6: 6516
  • 94 Morton D, Leach S, Cordier C, Warriner S, Nelson A. Angew. Chem. Int. Ed. 2009; 48: 104
  • 95 Robbins D, Newton AF, Gignoux C, Legeay J.-C, Sinclair A, Rejzek M, Laxon CA, Yalamanchili SK, Lewis W, O’Connell MA, Stockman RA. Chem. Sci. 2011; 2: 2232
  • 96 Brauch S, van Berkel SS, Westermann B. Chem. Soc. Rev. 2013; 42: 4948
  • 97 Zaretsky S, Hickey JL, Tan J, Pichugin D, St Denis MA, Ler S, Chung BK. W, Scully CC. G, Yudin AK. Chem. Sci. 2015; 6: 5446
  • 98 Wessjohann LA, Rivera DG, Vercillo OE. Chem. Rev. 2009; 109: 796
  • 99 Hung AW, Ramek A, Wang Y, Kaya T, Wilson JA, Clemons PA, Young DW. Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 6799
  • 100 Lovering F, Bikker J, Humblet C. J. Med. Chem. 2009; 52: 6752
  • 101 Aldeghi M, Malhotra S, Selwood DL, Chan AW. E. Chem. Biol. Drug Des. 2014; 83: 450
  • 102 Pelish HE, Westwood NJ, Feng Y, Kirchhausen T, Shair MD. J. Am. Chem. Soc. 2001; 123: 6740
  • 103 Huigens III RW, Morrison KC, Hicklin RW, Flood TA. Jr, Richter MF, Hergenrother PJ. Nat. Chem. 2013; 5: 195
  • 104 Rafferty RJ, Hicklin RW, Maloof KA, Hergenrother PJ. Angew. Chem. Int. Ed. 2013; 53: 220
  • 105 Lenci E, Menchi G, Trabocchi A. Org. Biomol. Chem. 2016; 14: 808
  • 106 Cumming JG, Davis AM, Muresan S, Haeberlein M, Chen H. Nat. Rev. Drug Discov. 2013; 12: 948
  • 107 Keller TH, Pichota A, Yin Z. Curr. Opin. Chem. Biol. 2006; 10: 357
  • 108 Kozakov D, Hall DR, Napoleon RL, Yeuh C, Whitty A, Vajda S. J. Med. Chem. 2015; 58: 9063
  • 109 Galloway WR. J. D, Spring DR. Nature 2011; 470: 43