Abstract

The lissoclimides are unusual succinimide-containing labdane diterpenoids that were reported to be potent cytotoxins. Our short semisynthesis and analogue-oriented synthesis approaches provide a series of lissoclimide natural products and analogues that expand the structure–activity relationships (SARs) in this family. The semisynthesis approach yielded significant quantities of chlorolissoclimide (CL) to permit an evaluation against the National Cancer Institute's 60-cell line panel and allowed us to obtain an X-ray co-crystal structure of the synthetic secondary metabolite with the eukaryotic 80S ribosome. Although it shares a binding site with other imide-based natural product translation inhibitors, CL engages in a particularly interesting and novel face-on halogen–π interaction between the ligand's alkyl chloride and a guanine residue. Our analogue-oriented synthesis provides many more lissoclimide compounds, which were tested against aggressive human cancer cell lines and for protein synthesis inhibitory activity. Finally, computational modelling was used to explain the SARs of certain key compounds and set the stage for the structure-guided design of better translation inhibitors.

  • Compound

    homoharringtonine

  • Compound

    cycloheximide

  • Compound

    chlorolissoclimide

  • Compound

    dichlorolissoclimide

  • Compound

    3-b-hydroxychlorolissoclimide

  • Compound

    haterumaimide A

  • Compound

    haterumaimide N

  • Compound

    haterumaimide Q

  • Compound

    haterumaimide E

  • Compound

    haterumaimide F

  • Compound

    haterumaimide J

  • Compound

    haterumaimide K

  • Compound

    lactimidomycin

  • Compound

    (+)-sclareolide

  • Compound

    (S,E)-1-(tert-butyldimethylsilyl)-7-(3,3-dimethyloxiran-2-yl)-5-methylhept-4-en-1-one

  • Compound

    2-(2-tosylethyl)-1,3-dioxolane

  • Compound

    tert-butyl(((2E,6E)-9-((S)-3,3-dimethyloxiran-2-yl)-1-(1,3-dioxolan-2-yl)-7-methylnona-2,6-dien-3-yl)oxy)dimethylsilane

  • Compound

    (1R,4aR,6S,8aS)-1-((1,3-dioxolan-2-yl)methyl)-6-((tert-butyldimethylsilyl)oxy)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one

  • Compound

    (1R,4aR,6S,8aS)-1-((1,3-dioxolan-2-yl)methyl)-6-hydroxy-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one

  • Compound

    (1R,4aS,8aS)-1-((1,3-dioxolan-2-yl)methyl)-5,5,8a-trimethyl-3,4,4a,5,8,8a-hexahydronaphthalen-2(1H)-one

  • Compound

    (((1R,4aS,8aS)-1-((1,3-dioxolan-2-yl)methyl)-5,5,8a-trimethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-2-yl)methyl)trimethylsilane

  • Compound

    2-((1R,3R,4aS,8aS)-3-bromo-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)acetaldehyde

  • Compound

    (R)-3-((S)-2-((1R,3R,4aS,8aS)-3-bromo-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)-1-hydroxyethyl)pyrrolidine-2,5-dione

  • Compound

    (E)-1-(tert-butyldimethylsilyl)-7-((2S,3S)-3-(((4-methoxybenzyl)oxy)methyl)-3-methyloxiran-2-yl)-5-methylhept-4-en-1-one

  • Compound

    (((2E,6E)-1-(1,3-dioxolan-2-yl)-9-((2S,3S)-3-(((4-methoxybenzyl)oxy)methyl)-3-methyloxiran-2-yl)-7-methylnona-2,6-dien-3-yl)oxy)(tert-butyl)dimethylsilane

  • Compound

    (1R,4aR,5R,6S,8aS)-1-((1,3-dioxolan-2-yl)methyl)-6-hydroxy-5-(((4-methoxybenzyl)oxy)methyl)-5,8a-dimethyloctahydronaphthalen-2(1H)-one

  • Compound

    (1R,4aR,5R,8aS)-1-((1,3-dioxolan-2-yl)methyl)-5-(hydroxymethyl)-5,8a-dimethyl-3,4,4a,5,8,8a-hexahydronaphthalen-2(1H)-one

  • Compound

    (1R,4aR,5R,8aS)-1-((1,3-dioxolan-2-yl)methyl)-6,7-dichloro-5-(hydroxymethyl)-5,8a-dimethyloctahydronaphthalen-2(1H)-one

  • Compound

    2-((1S,4aR,5R,6S,7S,8aR)-6,7-dichloro-5,8a-dimethyl-2-methylene-5-(((trimethylsilyl)oxy)methyl)decahydronaphthalen-1-yl)acetaldehyde

  • Compound

    2,3-β-dichloro-18-trimethylsilyletherdecalin

  • Compound

    2,3-α-dichloro-18-hydroxyhaterumaimide

  • Compound

    3-chloro-haterumaimide J

  • Compound

    7-desoxy-haterumaimide Q

  • Compound

    12,13-diepi-haterumaimide

  • Compound

    3-hydroxy-haterumaimide

  • Compound

    2,3-haterumaimidene

  • Compound

    2,3-haterumaimidene

  • Compound

    7-desoxy-chlorolissoclimide

  • Compound

    2,3-diepi-dichlorolissoclimide

  • Compound

    zefimide

  • Compound

    (2S,4R,4aS,6S,8aS)-6-chloro-4a,8,8-trimethyl-3-methylene-4-(2-oxoethyl)decahydronaphthalen-2-yl acetate

  • Compound

    (1S,4aR,6S,8aS)-1-((1,3-dioxolan-2-yl)methyl)-6-((tert-butyldimethylsilyl)oxy)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one

  • Compound

    (1R,4aS,8aS)-1-((1,3-dioxolan-2-yl)methyl)-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one

  • Compound

    (1R,4aS,8aS)-1-((1,3-dioxolan-2-yl)methyl)-5,5,8a-trimethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-2-yl trifluoromethanesulfonate

  • Compound

    2-(((1R,3R,4aS,8aS)-3-bromo-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl)-1,3-dioxolane

  • Compound

    (E)-5-((2S,3S)-3-hydroxy-3-methyloxiran-2-yl)-3-methylpent-2-en-1-yl benzoate

  • Compound

    (E)-5-((2S,3S)-3-(paramethoxybenzyl)-3-methyloxiran-2-yl)-3-methylpent-2-en-1-yl benzoate

  • Compound

    (E)-5-((2S,3S)-3-(paramethoxybenzyl)-3-methyloxiran-2-yl)-3-methylpent-2-en-1-ol

  • Compound

    (2S,3S)-3-((E)-5-bromo-3-methylpent-3-en-1-yl)-2-(paramethoxybenzyl)-2-methyloxirane

  • Compound

    (1S,4aR,5R,6S,8aS)-1-((1,3-dioxolan-2-yl)methyl)-6-hydroxy-5-(((4-methoxybenzyl)oxy)methyl)-5,8a-dimethyloctahydronaphthalen-2(1H)-one

  • Compound

    (1R,4aR,5R,8aS)-1-((1,3-dioxolan-2-yl)methyl)-5-(((4-methoxybenzyl)oxy)methyl)-5,8a-dimethyl-3,4,4a,5,8,8a-hexahydronaphthalen-2(1H)-one

  • Compound

    (1R,4aR,5R,8aS)-1-((1,3-dioxolan-2-yl)methyl)-6,7-dichloro-5,8a-dimethyl-5-(((trimethylsilyl)oxy)methyl)octahydronaphthalen-2(1H)-one

  • Compound

    (((1R,4aR,5S,8aR)-5-((1,3-dioxolan-2-yl)methyl)-2,3-dichloro-1,4a-dimethyl-6-methylenedecahydronaphthalen-1-yl)methoxy)trimethylsilane

  • Compound

    2-((1S,4aS,8aS)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)acetaldehyde

  • Compound

    (((2S,4aR,5S,8aR)-5-((1,3-dioxolan-2-yl)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalen-2-yl)oxy)(tert-butyl)dimethylsilane

  • Compound

    2-((1S,4aR,6S,8aR)-6-((tert-butyldimethylsilyl)oxy)-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)acetaldehyde

  • Compound

    3-silylether-haterumaimide

  • Compound

    (2S,4aR,5S,8aR)-5-((1,3-dioxolan-2-yl)methyl)-1,1,4a-trimethyl-6-methylenedecahydronaphthalen-2-ol

  • Compound

    2-(((1S,4aS,8aR)-5,5,8a-trimethyl-2-methylene-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-yl)methyl)-1,3-dioxolane

  • Compound

    2-((1S,4aS,8aR)-5,5,8a-trimethyl-2-methylene-1,2,3,4,4a,5,8,8a-octahydronaphthalen-1-yl)acetaldehyde

  • Compound

    (1R,4aR,6S,7S,8aS)-1-((1,3-dioxolan-2-yl)methyl)-6,7-dichloro-5,5,8a-trimethyloctahydronaphthalen-2(1H)-one

  • Compound

    (1R,4aR,6S,7S,8aS)-1-((1,3-dioxolan-2-yl)methyl)-6,7-dichloro-5,5,8a-trimethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-2-yl trifluoromethanesulfonate

  • Compound

    (((1R,4aR,6S,7S,8aR)-1-((1,3-dioxolan-2-yl)methyl)-6,7-dichloro-5,5,8a-trimethyl-1,4,4a,5,6,7,8,8a-octahydronaphthalen-2-yl)methyl)trimethylsilane

  • Compound

    2-(((1R,3R,4aR,6S,7S,8aS)-3-bromo-6,7-dichloro-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)methyl)-1,3-dioxolane

  • Compound

    2-((1R,3R,4aR,6S,7S,8aS)-3-bromo-6,7-dichloro-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)acetaldehyde

  • Compound

    2,3-α-dichloro-7-α-bromo-haterumaimide

  • Compound

    2-((1S,4aR,6S,7S,8aR)-6,7-dichloro-5,5,8a-trimethyl-2-methylenedecahydronaphthalen-1-yl)acetaldehyde

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    et al. One core, two shells: bacterial and eukaryotic ribosomes. Nat. Struct. Mol. Biol. 19, 560–567 (2012).

  2. 2.

    et al. eIF4E—from translation to transformation. Oncogene 23, 3172–3179 (2004).

  3. 3.

    et al. Measurement of tumour protein synthesis in vivo in human colorectal and breast cancer and its variability in separate biopsies from the same tumour. Clin. Sci. 80, 587–593 (1991).

  4. 4.

    , & Emerging therapeutics targeting mRNA translation. Cold Spring Harb. Perspect. Biol. 4, a012377 (2014).

  5. 5.

    , & Omacetaxine: a protein translation inhibitor for treatment of chronic myelogenous leukemia. Clin. Cancer Res. 20, 1735–1740 (2014).

  6. 6.

    , , , & Quantification of protein half-lives in the budding yeast proteome. Proc. Natl Acad. Sci. USA 103, 13004–13009 (2006).

  7. 7.

    , & Ribosome profiling of mouse embryonic stem cells reveals the complexity and dynamics of mammalian proteomes. Cell 147, 789–802 (2011).

  8. 8.

    et al. Decoding human cytomegalovirus. Science 338, 1088–1093 (2012).

  9. 9.

    et al. The structure of the eukaryotic ribosome at 3.0 Å resolution. Science 334, 1524–1529 (2011).

  10. 10.

    et al. Structural basis for the inhibition of the eukaryotic ribosome. Nature 513, 517–522 (2014).

  11. 11.

    et al. Dichlorolissoclimide, a new cytotoxic labdane derivative from Lissoclinum voeltzkowi Michaelson (Urochordata). Tetrahedron Lett. 32, 6701–6702 (1991).

  12. 12.

    , & Dichlorolissoclimide from Lissoclinum voeltzkowi Michaelson (Urochordata): crystal structure and absolute stereochemistry. J. Nat. Prod. 59, 1203–1204 (1996).

  13. 13.

    et al. Effects in vitro of two marine substances, chlorolissoclimide and dichlorolissoclimide, on a non-small-cell bronchopulmonary carcinoma cell line (MSCLC-N6). Anti-Cancer Drug Design 7, 493–502 (1992).

  14. 14.

    , , , & Cytotoxic labdane alkaloids from an ascidian Lissoclinum sp.: isolation, structure elucidation, and structure–activity relationship. Bioorg. Med. Chem. 14, 6954–6961 (2006).

  15. 15.

    , , , & Cytotoxic lissoclimide-type diterpenes from the molluscs Pleurobranchus albiguttatus and Pleurobranchus forskalii. J. Nat. Prod. 67, 1415–1418 (2004).

  16. 16.

    , , , & Haterumaimides J and K, potent cytotoxic diterpene alkaloids from the ascidian Lissoclinum species. Chem. Lett. 10, 1028–1029 (2002).

  17. 17.

    , , , & Haterumaimides F–I, four new cytotoxic diterpene alkaloids from an ascidian Lissoclinum species. J. Nat. Prod. 64, 1169–1173 (2001).

  18. 18.

    , , , & Haterumaimides A–E, five new dichlorolissoclimide-type diterpenoids from an ascidian Lissoclinum species. Heterocycles 54, 1039–1047 (2001).

  19. 19.

    et al. Chlorolissoclimides: new inhibitors of eukaryotic protein synthesis. RNA 12, 717–724 (2006).

  20. 20.

    et al. Inhibition of eukaryotic translation elongation by cycloheximide and lactimidomycin. Nat. Chem. Biol. 6, 209–217 (2010).

  21. 21.

    et al. Lactimidomycin, a new glutarimide group antibiotic. Production, isolation, structure and biological activity. J. Antibiot. 45, 1433–1441 (1992).

  22. 22.

    , , , & Iso-migrastatin congeners from Streptomyces platensis and generation of a glutarimide polyketide library featuring the dorrigocin, lactimidomycin, migrastatin, and NK30424 scaffolds. J. Am. Chem. Soc. 127, 11930–11931 (2005).

  23. 23.

    et al. Total syntheses and biological reassessment of lactidomycin, isomigrastatin and congener glutarimide antibiotics. Chem. Eur. J. 19, 7370–7383 (2013).

  24. 24.

    et al. Site-selective aliphatic C–H chlorination using N-chloroamides enables a synthesis of chlorolissoclimide. J. Am. Chem. Soc. 138, 696–702 (2016).

  25. 25.

    et al. A platform for the discovery of new macrolide antibiotics. Nature 533, 338–345 (2016).

  26. 26.

    COMPARE analysis (National Cancer Institute, accessed 24 March 2017), .

  27. 27.

    Actinomycin. chemistry and mechanism of action. Chem. Rev. 74, 625–652 (1974).

  28. 28.

    , , , & FR901228, a potent antitumor antibiotic, is a novel histone deacetylase inhibitor. Exper. Cell Res. 241, 126–133 (1998).

  29. 29.

    , , & Cl–π interactions in protein–ligand complexes. Protein Sci. 17, 1129–1137 (2008).

  30. 30.

    , & Generalized gradient approximation made simple Phys. Rev. Lett. 77, 3865–3868 (1996).

  31. 31.

    , & Effect of the damping function in dispersion corrected density functional theory J. Comput. Chem. 32, 1456–1465 (2011).

  32. 32.

    , & Enantioselective aldol condensations. 2. Erythro-selective chiral aldol condensations via boron enolates J. Am. Chem. Soc. 103, 2127–2129 (1981).

  33. 33.

    , , & Asymmetric aldol reactions under normal and inverse addition modes of the reagents. Chem. Commun. 2408–2410 (2007).

  34. 34.

    et al. A fast and straightforward route towards the synthesis of the lissoclimide class of anti-tumour agents. Tetrahedron 66, 9270–9276 (2010).

  35. 35.

    , , & First synthesis of lissoclimide-type alkaloids. Lett. Org. Chem. 6, 289–292 (2009).

  36. 36.

    & Extending the scope of the Evans asymmetric aldol reaction: preparation of anti and ‘non-Evans’ syn aldols. J. Org. Chem. 56, 5747–5750 (1991).

  37. 37.

    , & A simple enantioselective synthesis of the biologically active tetracyclic marine sesterterpene scalarenedial. J. Am. Chem. Soc. 119, 9927–9928 (1997).

  38. 38.

    , & Total synthesis of (+)-α-onocerin in four steps via four-component coupling and tetracyclization steps. J. Am. Chem. Soc. 124, 11290–11291 (2002).

  39. 39.

    , & Template-directed intramolecular C-glycosidation. Total synthesis of 2,3-dideoxy-D-manno-2-octopyranosonic acid. Tetrahedron Lett. 36, 5815–5818 (1995).

  40. 40.

    & Lithiated 3-tosylpropanal and 4-tosyl-2-butanone dimethyl acetals as β-acylvinyl anion equivalents for the synthesis of unsaturated 1,4-dicarbonyl compounds and α,β-butenolides. Tetrahedron 51, 2763–2776 (1995).

  41. 41.

    , & Efficient formal synthesis of (±)-axamide-1 and (±)-axisonitrile-1 via an intramolecular Hosomi–Sakurai reaction. Tetrahedron Lett. 51, 3542–3544 (2010).

  42. 42.

    & Ring-closing metathesis of allylsilanes as a flexible strategy toward cyclic terpenes. Short syntheses of teucladiol, isoteucladiol, poitediol and dactylol, and an attempted synthesis of caryophyllene. J. Org. Chem. 75, 6908–6922 (2010).

  43. 43.

    , & The reaction of superoxide with alkyl halides and tosylates. J. Org. Chem. 40, 1678–1680 (1975).

  44. 44.

    et al. Furan-terminated N-acyliminium ion initiated cyclizations in alkaloid synthesis. J. Org. Chem. 63, 6914–6928 (1998).

  45. 45.

    , , & Tetraethylammonium trichloride: a versatile reagent for chlorinations and oxidations. Angew. Chem. Int. Ed. 36, 2342–2344 (1997).

  46. 46.

    & A synthesis of the ABC tricyclic core of the clionastatins serves to corroborate their proposed structures. Org. Lett. 16, 1458–1461 (2014).

  47. 47.

    et al. Enantioselective, divergent syntheses of several polyhalogenated Plocamium monoterpenes and evaluation of their selectivity for solid tumors. Angew. Chem. Int. Ed. 53, 12205–12209 (2014).

  48. 48.

    , & Stereoselective dichlorination of allylic alcohol derivatives to access key stereochemical arrays of the chlorosulfolipids. J. Am. Chem. Soc. 130, 12514–12518 (2008).

  49. 49.

    , & Inhibitors of protein synthesis identified by a high throughput multiplexed translation screen. Nucleic Acids Res. 32, 902–915 (2004).

  50. 50.

    ROCS 3.2.1.4 (OpenEye Scientific Software, Sante Fe, New Mexico).

  51. 51.

    FRED pose prediction and virtual screening accuracy. J. Chem. Inf. Model. 51, 578–596 (2011).

  52. 52.

    & Autodock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comp. Chem. 31, 455–461 (2010).

  53. 53.

    , , & Structural aspects of messenger RNA reading frame maintenance by the ribosome. Nat. Struct. Mol. Biol. 17, 555–560 (2010).

Download references

Acknowledgements

Preliminary studies in the Vanderwal laboratory were supported by grants from the National Institutes of Health (NIH) and the University of California (UC) Cancer Research Coordinating Committee (GM-086483 and UCCRCC-55179, respectively, to C.D.V.). We acknowledge the Developmental Therapeutics Program of the National Cancer Institute for the evaluations of CL in the NCI-60 cell line panel. The work in the Yusupov laboratory was supported by the French National Research Agency ANR-15-CE11-0021-01 (to G.Y.), and by a European Research Council advanced grant 294312 (to S.P., M.M. and M.Y.). M.Y. thanks the Russian Government Program of Competitive Growth of Kazan Federal University. The Yusupov group is grateful to the staff of the PROXIMA 1 beamline at the synchrotron SOLEIL (France) and, in particular, to L. Chavas and P. Legrand for providing a rapid access and assisting with data collection. D.L.M. and C.Z. appreciate support from the NIH (GM-108889), and C.Z. was supported by a Brazilian Science Without Borders fellowship administered by Capes/LASPAU. The results from the Horne laboratory reported in this publication derived from work performed in the Drug Discovery and Structural Biology Core of City of Hope Comprehensive Cancer Center supported by the National Cancer Institute of the NIH under award number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Work in the Pelletier lab is supported by a Canadian Institutes of Health Research (CIHR) grant (FDN-148366). The work of V.O.V. from the laboratory of F. Furche (University of California Irvine Department of Chemistry) was supported by the National Science Foundation (CHE-1464828).

Author information

Author notes

    • Zef A. Könst
    • , Anne R. Szklarski
    •  & Simone Pellegrino

    These authors contributed equally.

Affiliations

  1. Department of Chemistry, University of California, 1102 Natural Sciences II, Irvine, California 92697-2025, USA

    • Zef A. Könst
    • , Anne R. Szklarski
    • , Sharon E. Michalak
    • , Vamsee K. Voora
    •  & Christopher D. Vanderwal
  2. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM U964, CNRS UMR7104, Université de Strasbourg, 67404 Illkirch, France

    • Simone Pellegrino
    • , Mélanie Meyer
    • , Gulnara Yusupova
    •  & Marat Yusupov
  3. Department of Pharmaceutical Sciences, University of California, Irvine, California 91010 92697, USA

    • Camila Zanette
    •  & David L. Mobley
  4. Department of Biochemistry, McGill University, Montréal, Québec H3G 1Y6, Canada

    • Regina Cencic
    •  & Jerry Pelletier
  5. Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, California 91010, USA

    • Sangkil Nam
    •  & David A. Horne

Authors

  1. Search for Zef A. Könst in:

  2. Search for Anne R. Szklarski in:

  3. Search for Simone Pellegrino in:

  4. Search for Sharon E. Michalak in:

  5. Search for Mélanie Meyer in:

  6. Search for Camila Zanette in:

  7. Search for Regina Cencic in:

  8. Search for Sangkil Nam in:

  9. Search for Vamsee K. Voora in:

  10. Search for David A. Horne in:

  11. Search for Jerry Pelletier in:

  12. Search for David L. Mobley in:

  13. Search for Gulnara Yusupova in:

  14. Search for Marat Yusupov in:

  15. Search for Christopher D. Vanderwal in:

Contributions

C.D.V. and M.Y. designed the research with assistance from Z.A.K., G.Y., D.L.M., J.P. and D.A.H. All the synthetic chemistry was performed by Z.A.K., A.R.S. and S.E.M. M.M. purified and crystallized the yeast 80S ribosome. S.P. and M.M. performed the data collection at the synchrotron source. S.P. carried out the data processing, structure determination and interpretation of the CL/80S structure, with inputs from M.M., G.Y. and M.Y. Computational studies were carried out by C.Z. and V.O.V., cytotoxicity experiments were performed by S.N. and translation-inhibition data were obtained by R.C. C.D.V. wrote the manuscript with contributions from all the authors; all the authors helped to refine the manuscript and approved the final version.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Marat Yusupov or Christopher D. Vanderwal.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    Supplementary information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nchem.2800

Further reading