CC BY-ND-NC 4.0 · Synthesis 2019; 51(01): 55-66
DOI: 10.1055/s-0037-1610368
short review
Copyright with the author

Guided by Evolution: Biology-Oriented Synthesis of Bioactive Compound Classes

George Karageorgis
a   Max-Planck-Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-str. 11, 44227 Dortmund, Germany   Email: herbert.waldmann@mpi-dortmund.mpg.de
b   Current address: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK
,
Herbert Waldmann  *
a   Max-Planck-Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-str. 11, 44227 Dortmund, Germany   Email: herbert.waldmann@mpi-dortmund.mpg.de
› Author Affiliations
Further Information

Publication History

Received: 29 August 2018

Accepted: 03 September 2018

Publication Date:
11 October 2018 (online)

   Permissions and Reprints All articles of this category


Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue

Abstract

Biology-oriented-synthesis (BIOS), is a chemocentric approach to identifying structurally novel molecules as tools for chemical biology and medicinal chemistry research. The vast chemical space cannot be exhaustively covered by synthetic chemistry. Thus, methods which reveal biologically relevant portions of chemical space are of high value. Guided by structural conservation in the evolution of both proteins and natural products, BIOS classifies bioactive compound classes in a hierarchical manner based on molecular architecture and bioactivity. Biologically relevant scaffolds inspire and guide the synthesis of BIOS libraries, which calls for the development of suitable synthetic methodologies. These compound collections have enriched biological relevance, leading to the discovery of bioactive small molecules. These potent and selective modulators allow the study of complex biological pathways and may serve as starting points for drug discovery programs. Thus, BIOS can also be regarded as a hypothesis-generating tool, guiding the design and preparation of novel, bioactive molecular scaffolds. This review elaborates the principles of BIOS and highlights selected examples of their application, which have in turn created future opportunities for the expansion of BIOS and its combination with fragment-based compound discovery for the identification of biologically relevant small molecules with unprecedented molecular scaffolds.

1 Introduction

2 Structural Classification of Natural Products

3 Implications and Opportunities for Biology-Oriented Synthesis

4 Applications of Biology-Oriented Synthesis

4.1 Chemical Structure and Bioactivity Guided Approaches

4.2 Natural-Product-Derived Fragment-Based Approaches

5 Conclusions and Outlook

Key words

natural products - bioorganic chemistry - stereoselective synthesis - high-throughput screening - combinatorial chemistry
 

  • References

  • 1 Zamir E. Bastiaens PI. H. Nat. Chem. Biol. 2008; 4: 643
    CrossrefPubMed
  • 2 Dobson CM. Nature 2004; 432: 824
  • 3 Gao M. Skolnick J. PLoS Comput. Biol. 2013; 9: e1003302
    CrossrefPubMed
  • 4 Patel SC. Bradley LH. Jinadasa SP. Hecht MH. Protein Sci. 2009; 18: 1388
    CrossrefPubMed
  • 5 Sadreyev RI. Grishin NV. BMC Struct. Biol. 2006; 6: 6
    CrossrefPubMed
  • 6 Newman DJ. Cragg GM. J. Nat. Prod. 2007; 70: 461
    CrossrefPubMed
  • 7 Lovering F. Bikker J. Humblet C. J. Med. Chem. 2009; 52: 6752
    CrossrefPubMed
  • 8 Ziegler S. Pries V. Hedberg C. Waldmann H. Angew. Chem. Int. Ed. 2013; 52: 2744
    CrossrefPubMed
  • 9 Koch MA. Schuffenhauer A. Scheck M. Wetzel S. Casaulta M. Odermatt A. Ertl P. Waldmann H. Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 17272
    CrossrefPubMed
  • 10 Murray CW. Rees DC. Nat. Chem. 2009; 1: 187
    CrossrefPubMed
  • 11 Renner S. van Otterlo WA. L. Dominguez Seoane M. Mocklinghoff S. Hofmann B. Wetzel S. Schuffenhauer A. Ertl P. Oprea TI. Steinhilber D. Brunsveld L. Rauh D. Waldmann H. Nat. Chem. Biol. 2009; 5: 585
    CrossrefPubMed
  • 12 Frye SV. Nat. Chem. Biol. 2010; 6: 159
    CrossrefPubMed
  • 13 Dückert H. Pries V. Khedkar V. Menninger S. Bruss H. Bird AW. Maliga Z. Brockmeyer A. Janning P. Hyman A. Grimme S. Schürmann M. Preut H. Hübel K. Ziegler S. Kumar K. Waldmann H. Nat. Chem. Biol. 2012; 8: 179
    CrossrefPubMed
  • 14 Ishikura M. Yamada K. Abe T. Nat. Prod. Rep. 2010; 27: 1630
    CrossrefPubMed
  • 15 Hung DT. Jamison TF. Schreiber SL. Chem. Biol. 1996; 3: 623
    CrossrefPubMed
  • 16 Peterson JR. Mitchison TJ. Chem. Biol. 2002; 9: 1275
    CrossrefPubMed
  • 17 Lim MJ. Wang XW. Cancer Detect. Prev. 2006; 30: 481
    CrossrefPubMed
  • 18 Hutten S. Kehlenbach RH. Trends Cell Biol. 2007; 17: 193
    CrossrefPubMed
  • 19 Eschenbrenner-Lux V. Küchler P. Ziegler S. Kumar K. Waldmann H. Angew. Chem. Int. Ed. 2014; 53: 2134
    CrossrefPubMed
  • 20 Enders D. Grondal C. Hüttl MR. M. Angew. Chem. Int. Ed. 2007; 46: 1570
    CrossrefPubMed
  • 21 Nielsen TE. Schreiber SL. Angew. Chem. Int. Ed. 2008; 47: 48
    CrossrefPubMed
  • 22 Liu W. Khedkar V. Baskar B. Schürmann M. Kumar K. Angew. Chem. Int. Ed. 2011; 50: 6900
    CrossrefPubMed
  • 23 Butler MS. Nat. Prod. Rep. 2008; 25: 475
    CrossrefPubMed
  • 24 Prisinzano TE. J. Nat. Prod. 2009; 72: 581
    CrossrefPubMed
  • 25 Jessen HJ. Schumacher A. Shaw T. Pfaltz A. Gademann K. Angew. Chem. Int. Ed. 2011; 50: 4222
    CrossrefPubMed
  • 26 Kuai L. Wang X. Madison JM. Schreiber SL. Scolnick EM. Haggarty SJ. ACS Chem. Neurosci. 2010; 1: 325
    CrossrefPubMed
  • 27 Bauer AJ. Stockwell BR. Chem. Rev. 2008; 108: 1774
    CrossrefPubMed
  • 28 Dakas P.-Y. Parga JA. Höing S. Schöler HR. Sterneckert J. Kumar K. Waldmann H. Angew. Chem. Int. Ed. 2013; 52: 9576
    CrossrefPubMed
  • 29 Praveen Kumar V. Gajendra Reddy R. Vo DD. Chakravarty S. Chandrasekhar S. Grée R. Bioorg. Med. Chem. Lett. 2012; 22: 1439
    CrossrefPubMed
  • 30 Cheng X. Harzdorf N. Khaing Z. Kang D. Camelio AM. Shaw T. Schmidt CE. Siegel D. Org. Biomol. Chem. 2012; 10: 383
    CrossrefPubMed
  • 31 Rawat M. Gama CI. Matson JB. Hsieh-Wilson LC. J. Am. Chem. Soc. 2008; 130: 2959
    CrossrefPubMed
  • 32 Antonchick AP. López-Tosco S. Parga J. Sievers S. Schürmann M. Preut H. Höing S. Schöler HR. Sterneckert J. Rauh D. Waldmann H. Chem. Biol. 2013; 20: 500
    CrossrefPubMed
  • 33 Chessari G. Woodhead AJ. Drug Discov. Today 2009; 14: 668
    CrossrefPubMed
  • 34 Roughley SD. Hubbard RE. J. Med. Chem. 2011; 54: 3989
    CrossrefPubMed
  • 35 Siegel MG. Vieth M. Drug Discov. Today 2007; 12: 71
    CrossrefPubMed
  • 36 Babaoglu K. Shoichet BK. Nat. Chem. Biol. 2006; 2: 720
    CrossrefPubMed
  • 37 Hung AW. Ramek A. Wang Y. Kaya T. Wilson JA. Clemons PA. Young DW. Proc. Natl. Acad. Sci. U.S.A. 2011; 108: 6799
    CrossrefPubMed
  • 38 Grabowski K. Baringhaus K.-H. Schneider G. Nat. Prod. Rep. 2008; 25: 892
    CrossrefPubMed
  • 39 Congreve M. Carr R. Murray C. Jhoti H. Drug Discov. Today 2003; 8: 876
    PubMed
  • 40 Köster H. Craan T. Brass S. Herhaus C. Zentgraf M. Neumann L. Heine A. Klebe G. J. Med. Chem. 2011; 54: 7784
    CrossrefPubMed
  • 41 Over B. Wetzel S. Grütter C. Nakai Y. Renner S. Rauh D. Waldmann H. Nat. Chem. 2013; 5: 21
    CrossrefPubMed
  • 42 Furstner A. Chem. Soc. Rev. 2009; 38: 3208
    CrossrefPubMed
  • 43 Blunt JW. Copp BR. Munro MH. G. Northcote PT. Prinsep MR. Nat. Prod. Rep. 2005; 22: 15
    CrossrefPubMed
  • 44 Galliford CV. Scheidt KA. Angew. Chem. Int. Ed. 2007; 46: 8748
    CrossrefPubMed
  • 45 Ding K. Lu Y. Nikolovska-Coleska Z. Wang G. Qiu S. Shangary S. Gao W. Qin D. Stuckey J. Krajewski K. Roller PP. Wang S. J. Med. Chem. 2006; 49: 3432
    CrossrefPubMed
  • 46 Pérez-Galán P. Martin NJ. A. Campaña AG. Cárdenas DJ. Echavarren AM. Chem. Asian J. 2011; 6: 482
    CrossrefPubMed
  • 47 López-Carrillo V. Huguet N. Mosquera Á. Echavarren AM. Chem. Eur. J. 2011; 17: 10972
    CrossrefPubMed
  • 48 Briscoe J. Therond PP. Nat. Rev. Mol. Cell Biol. 2013; 14: 416
  • 49 Anastas JN. Moon RT. Nat. Rev. Cancer 2013; 13: 11
    CrossrefPubMed
  • 50 Choi KS. Exp. Mol. Med. 2012; 44: 109
    CrossrefPubMed
  • 51 Jia ZJ. Shan G. Daniliuc CG. Antonchick AP. Waldmann H. Angew. Chem. Int. Ed. 2018; 1
  • 52 Edgar JA. Molyneux RJ. Colegate SM. Chem. Res. Toxicol. 2015; 28: 4
    CrossrefPubMed
  • 53 Robertson J. Stevens K. Nat. Prod. Rep. 2014; 31: 1721
    CrossrefPubMed
  • 54 Xu H. Golz C. Strohmann C. Antonchick AP. Waldmann H. Angew. Chem. Int. Ed. 2016; 55: 7761 ; Angew. Chem. 2016, 128, 7892
    CrossrefPubMed
  • 55 Singh S. Chem. Rev. 2000; 100: 925
    CrossrefPubMed
  • 56 Carroll FI. Runyon SP. Abraham P. Navarro H. Kuhar MJ. Pollard GT. Howard JL. J. Med. Chem. 2004; 47: 6401
    CrossrefPubMed
  • 57 Grynkiewicz G. Gadzikowska M. Pharmacol. Rep. 2008; 60: 439
    PubMed
  • 58 Cheenpracha S. Ritthiwigrom T. Laphookhieo S. J. Nat. Prod. 2013; 76: 723
    CrossrefPubMed
  • 59 O’Hagan D. Nat. Prod. Rep. 1997; 14: 637
    Crossref
  • 60 O’Hagan D. Nat. Prod. Rep. 2000; 17: 435
    CrossrefPubMed
  • 61 Jia ZJ. Takayama H. Futamura Y. Aono H. Bauer JO. Strohmann C. Antonchick AP. Osada H. Waldmann H. J. Org. Chem. 2018; 83: 7033
    CrossrefPubMed
  • 62 Zaima K. Koga I. Iwasawa N. Hosoya T. Hirasawa Y. Kaneda T. Ismail IS. Lajis NH. Morita H. J. Nat. Med. 2013; 67: 9
    CrossrefPubMed
  • 63 Rafferty RJ. Hicklin RW. Maloof KA. Hergenrother PJ. Angew. Chem. Int. Ed. 2014; 53: 220
    CrossrefPubMed
  • 64 Garcia-Castro M. Zimmermann S. Sankar MG. Kumar K. Angew. Chem. Int. Ed. 2016; 55: 7586
    CrossrefPubMed
  • 65 Morrison KC. Hergenrother PJ. Nat. Prod. Rep. 2014; 31: 6
    CrossrefPubMed
  • 66 Huigens RW. Morrison KC. Hicklin RW. Flood TA. Richter MF. Hergenrother PJ. Nat. Chem. 2013; 5: 195
    CrossrefPubMed
  • 67 Amirkia V. Heinrich M. Phytochem. Lett. 2014; 10: xlviii
    Crossref
  • 68 Laraia L. Ohsawa K. Konstantinidis G. Robke L. Wu Y.-W. Kumar K. Waldmann H. Angew. Chem. Int. Ed. 2017; 56: 2145
    CrossrefPubMed