Abstract
Nature offers a huge and only partially explored variety of small molecules with potential pharmaceutical applications. Commonly used characterization methods for natural products include spectroscopic techniques such as nuclear magnetic resonance spectroscopy and mass spectrometry. In some cases, however, these techniques do not succeed in the unambiguous determination of the chemical structure of unknown compounds. To validate the usefulness of scanning probe microscopy as an adjunct to the other tools available for organic structure analysis, we used the natural product cephalandole A, which had previously been misassigned, and later corrected. Our results, corroborated by density functional theory, demonstrate that direct imaging of an organic compound with atomic-resolution force microscopy facilitates the accurate determination of its chemical structure. We anticipate that our method may be developed further towards molecular imaging with chemical sensitivity, and will become generally useful in solving certain classes of natural product structures.
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References
Binnig, G. & Rohrer, H. Scanning tunneling microscopy. In Trends in Physics 1984 Proc. 6th Gen. Conf. Europ. Phys. Soc. Vol. 1 (eds Janta, J. & Pantoflíček, J.) 38–46 (EPS, 1984).
Driscoll, R. J., Youngquist, M. G. & Baldeschwieler, J. D. Atomic-scale imaging of DNA using scanning tunnelling microscopy. Nature 346, 294–296 (1991).
Heckl, W. et al. Two-dimensional ordering of the DNA base guanine observed by scanning tunneling microscopy. Proc. Natl Acad. Sci. USA 88, 8003–8005 (1991).
Otero, R. et al. Guanine quartet networks stabilized by cooperative hydrogen bonds. Angew. Chem. Int. Ed. 44, 2270–2275 (2005).
Shapir, E. et al. Electronic structure of single DNA molecules resolved by transverse scanning tunnelling spectroscopy. Nature Mater. 7, 68–74 (2008).
Tanaka, H. & Kawai, T. Partial sequencing of a single DNA molecule with a scanning tunnelling microscope. Nature Nanotech. 4, 518–522 (2009).
Baker, A. A., Helbert, W., Sugiyama, J. & Miles, M. J. New insight into cellulose structure by atomic force microscopy shows the Iα crystal phase at near-atomic resolution. Biophys. J. 79, 1139–1145 (2000).
Scheuring, S., Reiss-Husson, F., Engel, A., Rigaud, J. L. & Ranck, J. L. High-resolution AFM topographs of Rubrivivax gelatinosus light-harvesting complex LH2. EMBO J. 20, 3029–3035 (2001).
Gross, L., Mohn, F., Moll, N., Liljeroth, P. & Meyer, G. The chemical structure of a molecule resolved by atomic force microscopy. Science 325, 1110–1114 (2009).
Crews, P., Rodríguez, J. & Jaspars, M. Organic Structure Analysis (Oxford Univ. Press, 2010).
Blunt, J., Copp, B., Munro, M., Northcote, P. & Prinsep, M. Marine natural products. Nat. Prod. Rep. 27, 165–237 (2010).
Amagata, T. In Comprehensive Natural Products II Chemistry and Biology (eds Mander, L. & Lui, H.-W.) (Elsevier, 2010).
Nicolaou, K. C. & Snyder, S. A. Chasing molecules that were never there: misassigned natural products and the role of chemical synthesis in modern structure elucidation. Angew. Chem. Int. Ed. 44, 1012–1044 (2005).
Maier, M. E. Structural revisions of natural products by total synthesis. Nat. Prod. Rep. 26, 1105–1124 (2009).
Pathom-Aree, W. et al. Diversity of Actinomycetes isolated from Challenger Deep sediment (10,898 m) from the Mariana Trench. Extremophiles 10, 181–189 (2006).
Wu, P.-L., Hsu, Y.-L. & Jao, C.-W. Indole alkaloids from Cephalanceropsis gracilis. J. Nat. Prod. 69, 1467–1470 (2006).
Mason, J., Bergman, J. & Janosik, T. Synthetic studies of Cephalandole alkaloids and the revised structure of Cephalandole A. J. Nat. Prod. 71, 1447–1450 (2008).
Giessibl, F. J. High-speed force sensor for force microscopy and profilometry utilizing a quartz tuning fork. Appl. Phys. Lett. 73, 3956–3958 (1998); Erratum: Appl. Phys. Lett. 74, 4070 (1999).
Albrecht, T., Grütter, P., Horne, D. & Rugar, D. Frequency modulation detection using high-Q cantilevers for enhanced force microscope sensitivity. J. Appl. Phys. 69, 668–673 (1991).
Giessibl, F. J. Advances in atomic force microscopy. Rev. Mod. Phys. 75, 949–983 (2003).
Temirov, R., Soubatch, S., Neucheva, O., Lassise, A. & Tautz, F. A novel method achieving ultra-high geometrical resolution in scanning tunnelling microscopy. New J. Phys. 10, 053012 (2008).
Weiss, C. et al. Resolving chemical structures in scanning tunnelling microscopy. Preprint at http://arxiv.org/abs/0910.5825v1 (2010).
Sugimoto, Y. et al. Chemical identification of individual surface atoms by atomic force microscopy. Nature 446, 64–67 (2007).
Hohenberg, P. & Kohn, W. Inhomogeneous electron gas. Phys. Rev. 136, B864–B871 (1964).
Kohn, W. & Sham, L. J. Self-consistent equations including exchange and correlation effects. Phys. Rev. 140, A1133–A1138 (1965).
Keeling, D. L., Humphry, M. J., Fawcett, R. H. J., Beton, P. H., Hobbs, C. & Kantorovich, L. Bond breaking coupled with translation in rolling of covalently bound molecules. Phys. Rev. Lett. 94, 146104 (2005).
Moresco, F., Meyer, G., Rieder, K.-H., Tang, H., Gourdon, A. & Joachim, C. Conformational changes of single molecules induced by scanning tunneling microscopy manipulation: a route to molecular switching. Phys. Rev. Lett. 86, 672–675 (2001).
Theobald, J. A. et al. Controlling molecular deposition and layer structure with supramolecular surface assemblies. Nature 424, 1029–1031 (2003).
Champness, N. R. Molecular imaging: the tip of what can be seen. Nature Chem. 1, 597–598 (2009).
Mavrodi, D., Blankenfeldt, W. & Thomashow, L. Phenazine compounds in fluorescent Pseudomonas Spp. biosynthesis and regulation. Annu. Rev. Phytopathol. 44, 417–445 (2006).
Abdel-Mageed, W. et al. Dermacozines, a new phenazine family from deep-sea dermacocci isolated from a Mariana Trench sediment. Org. Biomol. Chem. doi: 10.1039/C001445A (2010).
CMPD, CPMD Consortium, Copyright IBM Corp. 1990–2008, Copyright MPI für Festkörperforschung Stuttgart 1997–2001.
Perdew, J. P., Burke, K. & Ernzerhof, M. Generalized gradient approximation made simple. Phys. Rev. Lett. 77, 3865–3868 (1996).
Hamann, D. R. Generalized norm-conserving pseudopotentials. Phys. Rev. B 40, 2980–2987 (1989).
Acknowledgements
The authors thank K. Horikoshi for providing the Mariana Trench sediment, and A. Bull and M. Goodfellow for providing the Dermacoccus abyssi strain. Thanks also go to A. Curioni and R. Allenspach for discussions and comments. The research leading to these results has received funding from the European Community's projects HERODOT (grant agreement no. 214954) and ARTIST (grant agreement no. 243421) and the Swiss National Center of Competence in Research (NCCR) ‘Nanoscale Science’. W.M.A.M. received a PhD scholarship from the Egyptian government, and Aberdeen University provided instrument access. M.J. is the recipient of a BBSRC Research Development fellowship. The EPSRC National Mass Spectrometry Service provided the MS data. M.J. acknowledges S. Jaspars for bringing the work of the IBM team to his attention.
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L.G., F.M. and G.M. performed the STM/AFM experiments. N.M. carried out the DFT calculations. R.E., W.M.A.M. and M.J. performed the NMR characterization and mass spectrometry. All authors contributed to the analysis of the data and the writing of the manuscript.
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Gross, L., Mohn, F., Moll, N. et al. Organic structure determination using atomic-resolution scanning probe microscopy. Nature Chem 2, 821–825 (2010). https://doi.org/10.1038/nchem.765
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DOI: https://doi.org/10.1038/nchem.765
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