ARTICLES
17. Kopp, F., Stratton, C. F., Akella, L. B. & Tan, D. S. A diversity-oriented synthesis
approach to macrocycles via oxidative ring expansion. Nature Chem. Biol. 8,
358–365 (2012).
18. Niggemann, J., Michaelis, K., Frank, R., Zander, N. & Hofle, G. Natural
product-derived building blocks for combinatorial synthesis. Part 1.
Fragmentation of natural products from myxobacteria. J. Chem. Soc. Perkin
Trans. 1, 2490–2503 (2002).
19. Lachance, H., Wetzel, S., Kumar, K. & Waldmann, H. Charting, navigating,
and populating natural product chemical space for drug discovery. J. Med. Chem.
55, 5989–6001 (2012).
20. Aquino, C. et al. A biomimetic polyketide-inspired approach to small-molecule
ligand discovery. Nature Chem. 4, 99–104 (2012).
21. O’Connor, S. E. & Maresh, J. J. Chemistry and biology of monoterpene indole
alkaloid biosynthesis. Nat. Prod. Rep. 23, 532–547 (2006).
22. Curtis, P. J. & Cross, B. E. Gibberellic acid. A new metabolite from the culture of
filtrates of Gibberella fujikuroi. Chem. Ind. 1066 (1954).
23. Rodrigues, C., Vandenberghe, L. P., de Oliveira, J. & Soccol, C. R. New
perspectives of gibberellic acid production: a review. Crit. Rev. Biotechnol. 32,
263–273 (2012).
24. Cross, B. E. Gibberellic acid. Part I. J. Chem. Soc. 4670–4676 (1954).
25. Mulholland, T. P. C. Gibberellic acid. Part 9. The structure of allogibberic acid.
J. Chem. Soc. 2693–2701 (1958).
26. Henderson, J. H. & Graham, H. D. A possible mechanism for biological and
chemical activity of gibberellic acid. Nature 193, 1055–1056 (1962).
27. Grove, J. F. & Mulholland, T. P. C. Gibberellic acid. Part 12. The stereochemistry
of allogibberic acid. J. Chem. Soc. 3007–3022 (1960).
28. Cross, B. E., Grove, J. F. & Morrison, A. Gibberellic acid. 18. Some
rearrangements of ring A. J. Chem. Soc. 2498–2515 (1961).
29. Cross, B. E. & Markwell, R. E. Rearrangements of the gibbane skeleton during
reactions with 2,3-dichloro-5,6-dicyanobenzoquinone. J. Chem. Soc. Perkin
Trans. I 1476–1487 (1973).
30. Idler, D. R., Schmidt, P. J. & Bitners, I. Isolation and identification of
adrenosterone in salmon (Oncorhynchus nerka) plasma. Can. J. Biochem.
Physiol. 39, 1653–1654 (1961).
31. Borthakur, M. & Boruah, R. C. A microwave promoted and Lewis acid catalysed
solventless approach to 4-azasteroids. Steroids 73, 637–641 (2008).
32. Bernstein, S., Littell, R. & Williams, J. H. Steroidal cyclic ketals. IV. The
conversion of 11-keto- to 11a-hydroxysteroids. The preparation of 11-epi-
hydrocortisone, and D4-androstene-11a-ol-3,17-dione. J. Am. Chem. Soc. 75,
1481–1482 (1953).
33. Lecomte, V., Stephan, E., LeBideau, F. & Jaouen, G. Improved addition of
organolithium reagents to hindered and/or enolisable ketones. Tetrahedron 59,
2169–2176 (2003).
34. Stephan, E., Brossat, M., Lecomte, V. & Bouit, P. A. Synthesis of the 11 beta-
hydroxymethyl-androst-4-en-3,17-dione. Tetrahedron 62, 3052–3055 (2006).
35. Song, C. E. Cinchona Alkaloids in Synthesis and Catalysis 1–10 (Wiley, 2009).
36. Smith, A. C. & Williams, R. M. Rabe rest in peace: confirmation of the rabe-
kindler conversion of D-quinotoxine into quinine: experimental affirmation of
the Woodward–Doering formal total synthesis of quinine. Angew. Chem. Int. Ed.
47, 1736–1740 (2008).
37. Hintermann, L., Schmitz, M. & Englert, U. Nucleophilic addition of
organometallic reagents to cinchona alkaloids: simple access to diverse
architectures. Angew. Chem. Int. Ed. 46, 5164–5167 (2007).
38. Baell, J. B. & Holloway, G. A. New substructure filters for removal of pan assay
interference compounds (PAINS) from screening libraries and for their
exclusion in bioassays. J. Med. Chem. 53, 2719–2740 (2010).
39. O’Shea, R. & Moser, H. E. Physicochemical properties of antibacterial
compounds: implications for drug discovery. J. Med. Chem. 51,
2871–2878 (2008).
transforms them into diverse compounds of equal complexity.
Beyond the three demonstrations herein, Supplementary Fig. S5
presents ten other complex and readily available natural products
that are highly suited to manipulation from complexity to diversity,
and this strategy is generalizable to scores of additional
natural products.
Certain chemical properties, such as molecular complexity and
multiple stereogenic centres, are extremely difficult to include
when large collections of compounds are produced for HTS. The
systematic application of ring-distortion reactions on appropriate
natural product starting materials offers a convenient approach to
the rapid generation of large numbers of complex and diverse
small molecules. These compounds possess a high degree of mol-
ecular complexity, as shown by examination of the Fsp3 and
number of stereogenic centres, and are diverse structurally, as indi-
cated by a Tanimoto similarity analysis. Depending on the exact
application, specific structural features (for example, molecular
mass, ClogP, hydrogen-bond donors/acceptors and so on) can be
programmed in by careful selection of diversification reactions
and building blocks. This method to construct complex and
diverse small molecules can rapidly provide compounds with
properties suitable for
medicinal applications.
a wide variety of biological and
Methods
Full experimental details and characterization data for all new compounds are
included in the Supplementary Information.
Received 12 October 2012; accepted 6 December 2012;
published online 20 January 2013
References
1. Swinney, D. C. & Anthony, J. How were new medicines discovered? Nature Rev.
Drug Discov. 10, 507–519 (2011).
2. Flaherty, K. T., Yasothan, U. & Kirkpatrick, P. Vemurafenib. Nature Rev. Drug
Discov. 10, 811–812 (2011).
3. Tsai, J. et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase
with potent antimelanoma activity. Proc. Natl Acad. Sci. USA 105,
3041–3046 (2008).
4. Domling, A. Small molecular weight protein–protein interaction antagonists: an
insurmountable challenge? Curr. Opin. Chem. Biol. 12, 281–291 (2008).
5. Grivas, P. D., Kiaris, H. & Papavassiliou, A. G. Tackling transcription factors:
challenges in antitumor therapy. Trends Mol. Med. 17, 537–538 (2011).
6. Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad
bugs: confronting the challenges of antibacterial discovery. Nature Rev. Drug
Discov. 6, 29–40 (2007).
7. Kodadek, T. The rise, fall and reinvention of combinatorial chemistry. Chem.
Commun. 47, 9757–9763 (2011).
8. Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug
discovery. Science 287, 1964–1969 (2000).
9. Galloway, W. R., Isidro-Llobet, A. & Spring, D. R. Diversity-oriented synthesis as
a tool for the discovery of novel biologically active small molecules. Nature
Commun. 1, 80 (2010).
10. Spaller, M. R., Burger, M. T., Fardis, M. & Bartlett, P. A. Synthetic strategies in
combinatorial chemistry. Curr. Opin. Chem. Biol. 1, 47–53 (1997).
11. Clemons, P. A. et al. Small molecules of different origins have distinct
distributions of structural complexity that correlate with protein-binding
profiles. Proc. Natl Acad. Sci. USA 107, 18787–18792 (2010).
12. Cui, J. et al. Creation and manipulation of common functional groups
en route to a skeletally diverse chemical library. Proc. Natl Acad. Sci. USA 108,
6763–6768 (2011).
40. Walters, W. P., Green, J., Weiss, J. R. & Murcko, M. A. What do medicinal
chemists actually make? A 50-year retrospective. J. Med. Chem. 54,
6405–6416 (2011).
41. Feher, M. & Schmidt, J. M. Property distributions: differences between drugs,
natural products, and molecules from combinatorial chemistry. J. Chem. Inf.
Comput. Sci. 43, 218–227 (2003).
42. Yan, A. & Gasteiger, J. Prediction of aqueous solubility of organic compounds
by topological descriptors. QSAR Comb. Sci. 22, 821–829 (2003).
43. Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation
as an approach to improving clinical success. J. Med. Chem. 52,
6752–6756 (2009).
44. Leeson, P. D. & St-Gallay, S. A. The influence of the ‘organizational factor’ on
compound quality in drug discovery. Nature Rev. Drug Discov. 10,
749–765 (2011).
13. Pelish, H. E., Westwood, N. J., Feng, Y., Kirchhausen, T. & Shair, M. D. Use of
biomimetic diversity-oriented synthesis to discover galanthamine-like molecules
with biological properties beyond those of the natural product. J. Am. Chem. Soc.
123, 6740–6741 (2001).
14. Goess, B. C., Hannoush, R. N., Chan, L. K., Kirchhausen, T. & Shair, M. D.
Synthesis of a 10,000-membered library of molecules resembling carpanone
and discovery of vesicular traffic inhibitors. J. Am. Chem. Soc. 128,
5391–5403 (2006).
45. Leeson, P. D. & Springthorpe, B. The influence of drug-like concepts on
decision-making in medicinal chemistry. Nature Rev. Drug Discov. 6,
881–890 (2007).
46. Rogers, D. J. & Tanimoto, T. T. A computer program for classifying plants.
Science 132, 1115–1118 (1960).
15. Kumar, N., Kiuchi, M., Tallarico, J. A. & Schreiber, S. L. Small-molecule diversity
using a skeletal transformation strategy. Org. Lett. 7, 2535–2538 (2005).
16. Balthaser, B. R., Maloney, M. C., Beeler, A. B., Porco, J. A. & Snyder, J. K.
Remodelling of the natural product fumagillol employing a reaction discovery
approach. Nature Chem. 3, 969–973 (2011).
7
© 2013 Macmillan Publishers Limited. All rights reserved.