Subscribe to RSS
Please copy the URL and add it into your RSS Feed Reader.
https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000083.xml
Synlett 2018; 29(14): 1823-1835
DOI: 10.1055/s-0037-1610242
DOI: 10.1055/s-0037-1610242
account
Emergent Properties of Natural Products
Financial support from the National Institutes of Health and Yale University is gratefully acknowledged.Further Information
Publication History
Received: 08 July 2018
Accepted after revision: 24 July 2018
Publication Date:
09 August 2018 (online)
Abstract
Emergence is the phenomenon by which novel properties arise from the combination of simpler fragments that lack those properties at their given levels of hierarchal complexity. Emergence is a centuries-old concept that is commonly invoked in biological systems. However, the penetration of this idea into chemistry, and studies of natural products in particular, has been more limited. In this article I will describe how the perspective of emergence provided a framework to elucidate the complex properties of two classes of natural products – the diazofluorene antitumor agent lomaiviticin A and the genotoxic bacterial metabolites known as colibactins, and sets the stage for a third class of molecules – antibiotics derived from the fungal metabolite pleuromutilin. Embracing the idea of emergence helped us to connect the aggregate reactivities of the colibactins and lomaiviticin A with their biological phenotypes. Emergence is a top-down approach to natural products and complements the classical bottom-up analysis of functional group structure and reactivity. It is a useful intellectual framework to study the complex evolved properties of natural products.
1 Introduction
2 Diazofluorenes
3 Precolibactins and Colibactins
4 Pleuromutilins
5 Discussion and Conclusion
-
References and Notes
- 1 Luisi PL. Found. Chem. 2002; 4: 183
- 2 Morgan CL. In Emergent Evolution: The Gifford Lectures Delivered in the University of St. Andrews in the Year 1922. Williams and Norgate; London: 1923
- 3 For a review, see: Aderem A. Cell 2005; 121: 511
- 4 For a discussion, see: Wilson RM. Danishefsky SJ. J. Org. Chem. 2006; 71: 8329
- 5 For a discussion, see: Wender PA. Verma VA. Paxton TJ. Pillow TH. Acc. Chem. Res. 2008; 41: 40
- 6 Tse WC. Boger DL. Chem. Biol. 2004; 11: 1607
- 7a Healy AR. Herzon SB. J. Am. Chem. Soc. 2017; 139: 14817
- 7b Herzon SB. Acc. Chem. Res. 2017; 50: 2577
- 7c Goethe O. Heuer A. Ma X. Wang Z. Herzon SB. Nat. Prod. Rep. 2018; in press:
- 8a Gould SJ. Chem. Rev. 1997; 97: 2499
- 8b Marco-Contelles J. Molina MT. Curr. Org. Chem. 2003; 7: 1433
- 8c Arya DP. Top. Heterocycl. Chem. 2006; 2: 129
- 8d Nawrat CC. Moody CJ. Nat. Prod. Rep. 2011; 28: 1426
- 8e Herzon SB. Woo CM. Nat. Prod. Rep. 2012; 29: 87
- 8f Herzon SB. The Kinamycins. In Total Synthesis of Natural Products: At the Frontiers of Organic Chemistry. Li JJ. Corey EJ. Springer; Berlin, Heidelberg: 2012: 39-65
- 9a Ito S. Matsuya T. Ōmura S. Otani M. Nakagawa A. J. Antibiot. 1970; 23: 315
- 9b Hata T. Ōmura S. Iwai Y. Nakagawa A. Otani M. J. Antibiot. 1971; 24: 353
- 9c Ōmura S. Nakagawa A. Yamada H. Hata T. Furusaki A. Watanabe T. Chem. Pharm. Bull. 1971; 19: 2428
- 9d Ōmura S. Nakagawa A. Yamada H. Hata T. Furusaki A. Watanabe T. Chem. Pharm. Bull. 1973; 21: 931
- 10 Seaton PJ. Gould SJ. J. Antibiot. 1989; 42: 189
- 11 He H. Ding WD. Bernan VS. Richardson AD. Ireland CM. Greenstein M. Ellestad GA. Carter GT. J. Am. Chem. Soc. 2001; 123: 5362
- 12 Furusaki A. Matsui M. Watanabe T. Ōmura S. Nakagawa A. Hata T. Isr. J. Chem. 1972; 10: 173
- 13a Lei X. Porco JA. J. Am. Chem. Soc. 2006; 128: 14790
- 13b Kumamoto T. Kitani Y. Tsuchiya H. Yamaguchi K. Seki H. Ishikawa T. Tetrahedron 2007; 63: 5189
- 13c Nicolaou KC. Li H. Nold AL. Pappo D. Lenzen A. J. Am. Chem. Soc. 2007; 129: 10356
- 13d Woo CM. Lu L. Gholap SL. Smith DR. Herzon SB. J. Am. Chem. Soc. 2010; 132: 2540
- 13e Scully SS. Porco JA. Angew. Chem. Int. Ed. 2011; 50: 9722
- 14a Woo CM. Beizer NE. Janso JE. Herzon SB. J. Am. Chem. Soc. 2012; 134: 15285
- 14b Kersten RD. Lane AL. Nett M. Richter TK. S. Duggan BM. Dorrestein PC. Moore BS. ChemBioChem 2013; 14: 955
- 15a Herzon SB. Lu L. Woo CM. Gholap SL. J. Am. Chem. Soc. 2011; 133: 7260
- 15b Woo CM. Gholap SL. Lu L. Kaneko M. Li Z. Ravikumar PC. Herzon SB. J. Am. Chem. Soc. 2012; 134: 17262
- 16 Colis LC. Woo CM. Hegan DC. Li Z. Glazer PM. Herzon SB. Nat. Chem. 2014; 6: 504
- 17 Xue M. Herzon SB. J. Am. Chem. Soc. 2016; 138: 15559
- 18 For a discussion of deoxyribose oxidation leading to strand cleavage, see: Burrows CJ. Muller JG. Chem. Rev. 1998; 98: 1109
- 19 Woo CM. Li Z. Paulson EK. Herzon SB. Proc. Natl. Acad. Sci. U.S.A. 2016; 113: 2851
- 20a Moore HW. Science 1977; 197: 527
- 20b Arya DP. Jebaratnam DJ. J. Org. Chem. 1995; 60: 3268
- 20c Mitra K. Kim W. Daniels JS. Gates KS. J. Am. Chem. Soc. 1997; 119: 11691
- 20d Laufer RS. Dmitrienko GI. J. Am. Chem. Soc. 2002; 124: 1854
- 20e Feldman KS. Eastman KJ. J. Am. Chem. Soc. 2005; 127: 15344
- 20f Feldman KS. Eastman KJ. J. Am. Chem. Soc. 2006; 128: 12562
- 20g Hasinoff BB. Wu X. Yalowich JC. Goodfellow V. Laufer RS. Adedayo O. Dmitrienko GI. Anti-Cancer Drugs 2006; 17: 825
- 20h Zeng W. Ballard TE. Tkachenko AG. Burns VA. Feldheim DL. Melander C. Bioorg. Med. Chem. Lett. 2006; 16: 5148
- 20i O'Hara KA. Wu X. Patel D. Liang H. Yalowich JC. Chen N. Goodfellow V. Adedayo O. Dmitrienko GI. Hasinoff BB. Free Radical Biol. Med. 2007; 43: 1132
- 20j Ballard TE. Melander C. Tetrahedron Lett. 2008; 49: 3157
- 20k Khdour O. Skibo EB. Org. Biomol. Chem. 2009; 7: 2140
- 20l Heinecke CL. Melander C. Tetrahedron Lett. 2010; 51: 1455
- 20m O'Hara KA. Dmitrienko GI. Hasinoff BB. Chem.-Biol. Interact. 2010; 184: 396
- 20n Mulcahy SP. Woo CM. Ding WD. Ellestad GA. Herzon SB. Chem. Sci. 2012; 3: 1070
- 20o Abbott GL. Wu X. Zhao Z. Guo L. Birman VB. Med. Chem. Commun. 2014; 5: 1364
- 21 Woo CM. Ranjan N. Arya DP. Herzon SB. Angew. Chem. Int. Ed. 2014; 53: 9325
- 22a Balskus EP. Nat. Prod. Rep. 2015; 32: 1534
- 22b Bode HB. Angew. Chem. Int. Ed. 2015; 54: 10408
- 22c Trautman EP. Crawford JM. Curr. Top. Med. Chem. 2015; 16: 1
- 22d Taieb F. Petit C. Nougayrède JP. Oswald E. EcoSal Plus 2016;
- 22e Gagnaire A. Nadel B. Raoult D. Neefjes J. Gorvel J.-P. Nat. Rev. Microbiol. 2017; 15: 109
- 23 Putze J. Hennequin C. Nougayrède JP. Zhang W. Homburg S. Karch H. Bringer MA. Fayolle C. Carniel E. Rabsch W. Oelschlaeger TA. Oswald E. Forestier C. Hacker J. Dobrindt U. Infect. Immun. 2009; 77: 4696
- 24a Dubois D. Baron O. Cougnoux A. Delmas J. Pradel N. Boury M. Bouchon B. Bringer MA. Nougayrède JP. Oswald E. Bonnet R. J. Biol. Chem. 2011; 286: 35562
- 24b Cougnoux A. Gibold L. Robin F. Dubois D. Pradel N. Darfeuille-Michaud A. Dalmasso G. Delmas J. Bonnet R. J. Mol. Biol. 2012; 424: 203
- 25 Nougayrède J.-P. Homburg S. Taieb F. Boury M. Brzuszkiewicz E. Gottschalk G. Buchrieser C. Hacker J. Dobrindt U. Oswald E. Science 2006; 313: 848
- 26 Cuevas-Ramos G. Petit CR. Marcq I. Boury M. Oswald E. Nougayrède J.-P. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 11537
- 27a Arthur JC. Perez-Chanona E. Mühlbauer M. Tomkovich S. Uronis JM. Fan T.-J. Campbell BJ. Abujamel T. Dogan B. Rogers AB. Rhodes JM. Stintzi A. Simpson KW. Hansen JJ. Keku TO. Fodor AA. Jobin C. Science 2012; 338: 120
- 27b Buc E. Dubois D. Sauvanet P. Raisch J. Delmas J. Darfeuille-Michaud A. Pezet D. Bonnet R. PLoS One 2013; 8: e56964
- 28 Bonnet M. Buc E. Sauvanet P. Darcha C. Dubois D. Pereira B. Déchelotte P. Bonnet R. Pezet D. Darfeuille-Michaud A. Clin. Cancer Res. 2014; 20: 859
- 29 Vizcaino MI. Crawford JM. Nat. Chem. 2015; 7: 411
- 30 Healy AR. Nikolayevskiy H. Patel JR. Crawford JM. Herzon SB. J. Am. Chem. Soc. 2016; 138: 15563
- 31a Brotherton CA. Balskus EP. J. Am. Chem. Soc. 2013; 135: 3359
- 31b Bian X. Fu J. Plaza A. Herrmann J. Pistorius D. Stewart AF. Zhang Y. Muller R. ChemBioChem 2013; 14: 1194
- 31c Vizcaino MI. Engel P. Trautman E. Crawford JM. J. Am. Chem. Soc. 2014; 136: 9244
- 32 Engel P. Vizcaino MI. Crawford JM. Appl. Environ. Microbiol. 2015; 81: 1502
- 33 Li ZR. Li Y. Lai JY. Tang J. Wang B. Lu L. Zhu G. Wu X. Xu Y. Qian PY. ChemBioChem 2015; 16: 1715
- 34 Zha L. Wilson MR. Brotherton CA. Balskus EP. ACS Chem. Biol. 2016; 11: 1287
- 35 Li ZR. Li J. Gu JP. Lai JY. Duggan BM. Zhang WP. Li ZL. Li YX. Tong RB. Xu Y. Lin DH. Moore BS. Qian PY. Nat. Chem. Biol. 2016; 12: 773
- 36 Brachmann AO. Garcie C. Wu V. Martin P. Ueoka R. Oswald E. Piel J. Chem. Commun. 2015; 51: 13138
- 37 Healy AR. Vizcaino MI. Crawford JM. Herzon SB. J. Am. Chem. Soc. 2016; 138: 5426
- 38 For a review, see: Tichenor MS. Boger DL. Nat. Prod. Rep. 2008; 25: 220
- 39 Deacylation of 14, 11, or 12c converts the amide into a primary amine, which will increase the affinity of the molecules for DNA.
- 40 Trautman EP. Healy AR. Shine EE. Herzon SB. Crawford JM. J. Am. Chem. Soc. 2017; 139: 4195
- 41 Bossuet-Greif N. Vignard J. Taieb F. Mirey G. Dubois D. Petit C. Oswald E. Nougayrède J.-P. mBio 2018; 9: e02393-17
- 42 Bian X. Plaza A. Zhang Y. Müller R. Chem. Sci. 2015; 6: 3154
- 43 For a discussion, see: Martens E. Demain AL. J. Antibiot. 2017; 70: 520
- 44 Charest MG. Siegel DR. Myers AG. J. Am. Chem. Soc. 2005; 127: 8292
- 45 Charest MG. Lerner CD. Brubaker JD. Siegel DR. Myers AG. Science 2005; 308: 395
- 46 For a review, see: Liu F. Myers AG. Curr. Opin. Chem. Biol. 2016; 32: 48
- 47 Okano A. Isley NA. Boger DL. Chem. Rev. 2017; 117: 11952
- 48 Seiple IB. Zhang Z. Jakubec P. Langlois-Mercier A. Wright PM. Hog DT. Yabu K. Allu SR. Fukuzaki T. Carlsen PN. Kitamura Y. Zhou X. Condakes ML. Szczypiński FT. Green WD. Myers AG. Nature 2016; 533: 338
- 49 Li Q. Seiple IB. J. Am. Chem. Soc. 2017; 139: 13304
- 50 https://www.nytimes.com/2007/10/17/us/17school-cnd.html.
- 51 Daum RS. Kar S. Kirkpatrick P. Nat. Rev. Drug Discovery 2007; 6: 865
- 52a Kavanagh F. Hervey A. Robbins WJ. Proc. Natl. Acad. Sci. U.S.A. 1951; 37: 570
- 52b Kavanagh F. Hervey A. Robbins WJ. Proc. Natl. Acad. Sci. U.S.A. 1952; 38: 555
- 52c Anchel M. J. Biol. Chem. 1952; 199: 133
- 52d Arigoni D. Gazz. Chim. Ital. 1962; 92: 884
- 52e Birch AJ. Holzapfel CW. Rickards RW. Tetrahedron 1966; 22: 359
- 52f Bonavia G. Pleuromutilin: Stereochemie und detaillierte Biosynthese. Thesis, ETH; Zürich: 1968
- 53 Lefamulin Evaluation Against Pneumonia (LEAP 2) Phase 3 Topline Results, https://investors.nabriva.com/static-files/5c34b447-99cc-4739-b9d6-d4ea4c7d13b9 (accessed 2018/06/20).
- 54a Schlunzen F. Pyetan E. Fucini P. Yonath A. Harms JM. Mol. Microbiol. 2004; 54: 1287
- 54b Davidovich C. Bashan A. Auerbach-Nevo T. Yaggie RD. Gontarek RR. Yonath A. Proc. Natl. Acad. Sci. U.S.A. 2007; 104: 4291
- 54c Eyal Z. Matzov D. Krupkin M. Paukner S. Riedl R. Rozenberg H. Zimmerman E. Bashan A. Yonath A. Sci. Rep. 2016; 6: 39004
- 55a Murphy SK. Zeng M. Herzon SB. Org. Lett. 2016; 18: 4880
- 55b Murphy SK. Zeng M. Herzon SB. Science 2017; 356: 956
- 55c Murphy SK. Zeng M. Herzon SB. Org. Lett. 2017; 19: 4980
- 55d Zeng M. Murphy SK. Herzon SB. J. Am. Chem. Soc. 2017; 139: 16377
- 56a Gibbons EG. J. Am. Chem. Soc. 1982; 104: 1767
- 56b Boeckman RK. Springer DM. Alessi TR. J. Am. Chem. Soc. 1989; 111: 8284
- 56c Fazakerley NJ. Helm MD. Procter DJ. Chem. Eur. J. 2013; 19: 6718
- 56d Farney EP. Feng SS. Schafers F. Reisman SE. J. Am. Chem. Soc. 2018; 140: 1267
- 57a Moslin RM. Miller-Moslin K. Jamison TF. Chem. Commun. 2007; 4441
- 57b Shareef A.-R. Sherman DH. Montgomery J. Chem. Sci. 2012; 3: 892
- 57c Wang H. Negretti S. Knauff AR. Montgomery J. Org. Lett. 2015; 17: 1493
- 57d Jackson EP. Malik HA. Sormunen GJ. Baxter RD. Liu P. Wang H. Shareef A.-R. Montgomery J. Acc. Chem. Res. 2015; 48: 1736
- 58 Berner H. Vyplel H. Schulz G. Schneider H. Monatsh. Chem. 1986; 117: 1073
- 59a Paukner S. Gruss A. Fritsche TR. Ivezic-Schoenfeld Z. Jones RN. In Vitro Activity of the Novel Pleuromutilin BC-3781 Tested Against Bacterial Pathogens Causing Sexually Transmitted Diseases (STD). 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy; Denver, CO: 2013
- 59b Paukner S. Strickmann DB. Ivezic-Schoenfeld Z. Extended Spectrum Pleuromutilins: Mode-of-action Studies . 24th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); Barcelona: 2014
- 59c Wicha WW. Ivezic-Schoenfeld Z. In Vivo Activity of Extended Spectrum Pleuromutilins in Murine Sepsis Model . 24th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); Barcelona: 2014
- 59d Paukner S. Kollmann H. Riedl R. Ivezic-Schoenfeld Z. Kill Curves of the Novel Extended-Spectrum Pleuromutilin Antibiotic BC-9529 . 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); Copenhagen: 2015
- 59e Paukner S. Wicha WW. Heilmayer W. Thirring K. Riedl R. Extended Spectrum Pleuromutilins: Potent Translation Inhibitors with Broad-Spectrum Antibacterial Activity In Vitro an In Vivo, Interscience Conference of Antimicrobial Agents and Chemotherapy. International Congress of Chemotherapy and Infection (ICAAC/ICC); San Diego / CA: 2015
- 59f Paukner S. Wicha WW. Thirring K. Kollmann H. Ivezic-Schoenfeld Z. In Vitro and In Vivo Efficacy of Novel Extended Spectrum Pleuromutilins Against S. aureus and S. pneumoniae . 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); Copenhagen: 2015
- 59g Thirring K. Heilmayer W. Riedl R. Kollmann H. Ivezic-Schoenfeld Z. Wicha W. Paukner S. Strickmann D. WO 2015110481A1, 2015
- 59h Wicha WW. Paukner S. Strickmann DB. Thirring K. Kollmann H. Heilmayer W. Ivezic-Schoenfeld Z. Efficacy of Novel Extended Spectrum Pleuromutilins Against E. coli In Vitro and In Vivo . 25th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID); Copenhagen: 2015
- 60a Bailey AM. Alberti F. Kilaru S. Collins CM. de Mattos-Shipley K. Hartley AJ. Hayes P. Griffin A. Lazarus CM. Cox RJ. Willis CL. O’Dwyer K. Spence DW. Foster GD. Sci. Rep. 2016; 6: 25202
- 60b Alberti F. Khairudin K. Venegas ER. Davies JA. Hayes PM. Willis CL. Bailey AM. Foster GD. Nat. Commun. 2017; 8: 1831
- 61 Ma X. Kucera R. Goethe OF. Murphy SK. Herzon SB. J. Org. Chem. 2018; 83: 6843
- 62 Simmons EM. Hartwig JF. Nature 2012; 483: 70
For a review of precolibactins and colibactins, see:
For a recent review of the mechanism of action of (–)-lomaiviticin A (4), see:
For a review of pleuromutilins, see:
For reviews, see:
For reviews, see: