Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Lessons from natural molecules

Nature volume 432, pages 829–837 (2004)Cite this article

Abstract

Natural products have inspired chemists and physicians for millennia. Their rich structural diversity and complexity has prompted synthetic chemists to produce them in the laboratory, often with therapeutic applications in mind, and many drugs used today are natural products or natural-product derivatives. Recent years have seen considerable advances in our understanding of natural-product biosynthesis. Coupled with improvements in approaches for natural-product isolation, characterization and synthesis, these could be opening the door to a new era in the investigation of natural products in academia and industry.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Medically significant natural products and synthetic molecules.
Figure 2: Natural products that exploit reactive functional groups.
Figure 3: Natural products that exploit shape and polarity complementarity to biological targets.
Figure 4: Template diversification.
Figure 5: Biosynthesis of natural products.
Figure 6: The role of oxidation in the construction of natural products.
Figure 7: Recent natural products obtained from nontraditional sources.

Similar content being viewed by others

References

  1. Newman, D. J., Cragg, G. M. & Snader, K. M. The influence of natural products upon drug discovery. Nat. Prod. Rep. 17, 215–234 (2000).

    Article  CAS  Google Scholar 

  2. Newman, D. J., Cragg, G. M., Holbeck, S. & Sausville, E. A. Natural products and derivatives as leads to cell cycle pathway targets in cancer chemotherapy. Curr. Cancer Drug Targets 2, 279–308 (2002).

    Article  CAS  Google Scholar 

  3. Newman, D. J., Cragg, G. M. & Snader, K. M. Natural products as sources of new drugs over the period 1981–2002. J. Nat. Prod. 66, 1022–1037 (2003).

    Article  CAS  Google Scholar 

  4. Altmann, K. -H. Microtubule-stabilizing agents: a growing class of important anticancer drugs. Curr. Opin. Chem. Biol. 5, 424–431 (2001).

    Article  CAS  Google Scholar 

  5. Mickel, S. J. et al. Large-scale synthesis of the anti-cancer marine natural product (+)–discodermolide. Part 1: Synthetic strategy and preparation of a common precursor. Org. Proc. Res. Dev. 8, 92–100 (2004).

    Article  CAS  Google Scholar 

  6. Sheldrick, G. M., Jones, P. G., Kennard, O., Williams, D. H. & Smith, G. A. Structure of vancomycin and its complex with acetyl-D-alanyl-D-alanine. Nature 271, 223–225 (1978).

    Article  ADS  CAS  Google Scholar 

  7. Williamson, M. P. & Williams, D. H. Structure revision of the antibiotic vancomycin. Use of nuclear Overhauser effect difference spectroscopy. J. Am. Chem. Soc. 103, 6580–6585 (1981).

    Article  CAS  Google Scholar 

  8. Furasaki, A. et al. The crystal and molecular structure of staurosporine, a new alkaloid from a Streptomyces strain. J. Chem. Soc. Chem. Commun. 800–801 (1978).

  9. Sehgal, S. N., Baker, H. & Vezina, C. Rapamycin (AY-22,989), a new antifungal antibiotic. II. Fermentation, isolation and characterization. J. Antibiot. 28, 727–732 (1975).

    Article  CAS  Google Scholar 

  10. Wani, M. C., Taylor, H. L., Wall, M. E., Coggon, P. & McPhail, A. T. The isolation and structure of taxol, a novel antileukemic and antitumor agent. J. Am. Chem. Soc. 93, 2325–2327 (1971).

    Article  CAS  Google Scholar 

  11. Pindur, U., Kim, Y. S. & Mehrabani, F. Advances in indolo[2,3-a]carbazole chemistry: design and synthesis of protein kinase C and topoisomerase I inhibitors. Curr. Med. Chem. 6, 29–69 (1999).

    CAS  PubMed  Google Scholar 

  12. Carson, C. C. 3rd Sildenafil: a 4-year update in the treatment of 20 million erectile dysfunction patients. Curr. Urol. Rep. 4, 488–496 (2003).

    Article  Google Scholar 

  13. Wong, D. T. & Bymaster, F. P. Development of antidepressant drugs. Fluoxetine (Prozac) and other selective serotonin uptake inhibitors. Adv. Exp. Med. Biol. 363, 77–95 (1995).

    Article  CAS  Google Scholar 

  14. Roth, B. D. The discovery and development of atorvastatin, a potent novel hypolipidemic agent. Prog. Med. Chem. 40, 1–22 (2002).

    Article  CAS  Google Scholar 

  15. Kurzrock, R., Kantarjian, H. M., Druker, B. J. & Talpaz, M. Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics. Ann. Intern. Med. 138, 819–830 (2003).

    Article  CAS  Google Scholar 

  16. Lee, M. D., Dunne, T. M., Chang, C. C., Morton, G. O. & Borders, D. B. Calicheamicins, a novel family of antitumor antibiotics. J. Am. Chem. Soc. 109, 3464–3466 (1987).

    Article  CAS  Google Scholar 

  17. Konishi, M. et al. Crystal and molecular structure of dynemicin A: a novel 1,5-diyn-3-ene antitumor antibiotic. J. Am. Chem. Soc. 112, 3715–3716 (1990).

    Article  CAS  Google Scholar 

  18. Thorson, J. S. et al. Understanding and exploiting nature's chemical arsenal: the past, present and future of calicheamicin research. Curr. Pharm. Des. 6, 1841–1879 (2000).

    Article  CAS  Google Scholar 

  19. Scotto, K. W. ET-743: more than an innovative mechanism of action. Anticancer Drugs 13 (Suppl. 1), S3–6 (2002).

    MathSciNet  CAS  PubMed  Google Scholar 

  20. Aune, G. J., Furuta, T. & Pommier, Y. Ecteinascidin 743: a novel anticancer drug with a unique mechanism of action. Anticancer Drugs 13, 545–555 (2002).

    Article  CAS  Google Scholar 

  21. Liu, S., Widom, J., Kemp, C. W., Crews, C. M. & Clardy, J. Structure of human methionine aminopeptidase-2 complexed with fumagillin. Science 282, 1324–1327 (1998).

    Article  ADS  CAS  Google Scholar 

  22. Meng, L., Kwok, B. H., Sin, N. & Crews, C. M. Eponemycin exerts its antitumor effect through the inhibition of proteasome function. Cancer Res. 59, 2798–2801 (1999).

    CAS  PubMed  Google Scholar 

  23. Fenteany, G. et al. Inhibition of proteasome activities and subunit-specific amino-terminal threonine modification by lactacystin. Science 268, 726–731 (1995).

    Article  ADS  CAS  Google Scholar 

  24. Feling, R. H. et al. Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew. Chem. Int. Edn Engl. 42, 355–357 (2003).

    Article  CAS  Google Scholar 

  25. Kim, M. Y., Gleason-Guzman, M., Izbicka, E., Nishioka, D. & Hurley, L. H. The differential biological effects of telomestatin and TMPPyP4 can be attributed to their selectivity for interaction with intramolecular and intermolecular G-quadruplex structures. Cancer Res. 63, 3247–3256 (2003).

    CAS  PubMed  Google Scholar 

  26. Choi, J., Chen, J., Schreiber, S. L. & Clardy, J. Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP. Science 273, 239–242 (1996).

    Article  ADS  CAS  Google Scholar 

  27. Gunasekera, S. P., Gunasekera, M., Longley, R. E. & Schulte, G. K. Discodermolide: a new bioactive polyhydroxylated lactone from the marine sponge Discodermia dissoluta. J. Org. Chem. 55, 4912–4915 (1991).

    Article  Google Scholar 

  28. Talpir, R., Benayahu, Y., Kashman, Y., Pannell, L. & Schleyer, M. Hemiasterlin and geodiamolide TA: two new cytotoxic peptides from the marine sponge Hemiasterella minor. Tetrahedron Lett. 35, 4453–4456 (1994).

    Article  CAS  Google Scholar 

  29. Anderson, R. J., Coleman, J. E., Andersen, R. J. & Roberge, M. Cytotoxic peptides hemiasterlin, hemiasterlin A and hemiasterlin B induce mitotic arrest and abnormal spindle formation. Cancer Chemother. Pharmacol. 39, 223–226 (1997).

    Article  CAS  Google Scholar 

  30. Schantz, E. J. et al. The structure of saxitoxin. J. Am. Chem. Soc. 93, 7344–7345 (1975).

    Google Scholar 

  31. Yotsu-Yamashita, M. et al. The structure of zetekitoxin AB, a saxitoxin analog from the Panamanian golden frog Atelopus zeteki: a potent sodium-channel blocker. Proc. Natl Acad. Sci. USA 101, 4346–4351 (2004).

    Article  ADS  CAS  Google Scholar 

  32. Rinehart, K. L. et al. Ecteinascidins 729, 743, 745, 759A, 759B and 770: potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata. J. Org. Chem. 55, 4512–4515 (1990).

    Article  CAS  Google Scholar 

  33. Boghaert, E. R. et al. Antibody-targeted chemotherapy with the calicheamicin conjugate hu3S193-N-acetyl gamma calicheamicin dimethyl hydrazide targets Lewisy and eliminates Lewisy-positive human carcinoma cells and xenografts. Clin. Cancer Res. 10, 4538–4549 (2004).

    Article  CAS  Google Scholar 

  34. DiJoseph, J. F. et al. Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood 103, 1807–1814 (2004).

    Article  CAS  Google Scholar 

  35. Boldi, A. M. Libraries from natural product-like scaffolds. Curr. Opin. Chem. Biol. 8, 281–286 (2004).

    Article  CAS  Google Scholar 

  36. Gunasekera, S. P., McCarthy, P. J., Kelly-Borges, M., Lobkovsky, E. & Clardy, J. Dysidiolide: a novel protein phosphatase inhibitor from the Caribbean sponge Dysidea etheria de Laubenfels. J. Am. Chem. Soc. 118, 8759–8760 (1996).

    Article  CAS  Google Scholar 

  37. Brohm, D. et al. Natural products are biologically validated starting points in structural space for compound library development: solid-phase synthesis of dysidiolide-derived phosphatase inhibitors. Angew. Chem. Int. Edn Engl. 41, 307–311 (2002).

    Article  CAS  Google Scholar 

  38. Schreiber, S. L. Target-oriented and diversity-oriented organic synthesis in drug discovery. Science 287, 1964–1969 (2000).

    Article  ADS  CAS  Google Scholar 

  39. Burke, M. D. & Schreiber, S. L. A planning strategy for diversity-oriented synthesis. Angew. Chem. Int. Edn Engl. 43, 46–58 (2004).

    Article  Google Scholar 

  40. Burke, M. D., Berger, E. M., Schreiber, S. L. Generating diverse skeletons of small molecules combinatorially. Science 302, 613–618 (2004).

    Article  ADS  Google Scholar 

  41. Walsh, C. Antibiotics: Actions, Origins, Resistance (ASM, Washington, 2003).

    Book  Google Scholar 

  42. Hubbard, B., Walsh, C. Vancomycin assembly: Nature's way. Angew. Chem. Int. Edn Engl. 730–765 (2003).

  43. Schwarzer, D., Firking, R., Marahiel, M. A. Nonribosomal peptides: from genes to products. Nat. Prod. Rep. 20, 275–287 (2003).

    Article  CAS  Google Scholar 

  44. Walsh, C., Freel Meyers, C. L., Losey, H. C. Antibiotic glycosyltransferases: antibiotic maturation and prospects for reprogramming. J. Med. Chem. 46, 3425–3436 (2003).

    Article  CAS  Google Scholar 

  45. Wendt, K. U., Schulz, G. E., Corey, E. J., Liu, D. R. Enzyme mechanisms for polycyclic triterpene formation. Angew. Chem. Int. Edn Engl. 39, 2812–2833 (2000).

    Article  CAS  Google Scholar 

  46. Whittington, D. A. et al. Bornyl diphosphate synthase: structure and strategy for carbocation manipulation by a terpenoid cyclase. Proc. Natl. Acad. Sci. USA 99, 15375–15380 (2002).

    Article  ADS  CAS  Google Scholar 

  47. Rawlings, B. J. Type I polyketide biosynthesis in bacteria (part A). Nat. Prod. Rep. 18, 190–230 (2001).

    Article  CAS  Google Scholar 

  48. Rawlings, B. J. Type I polyketide biosynthesis in bacteria (part B). Nat. Prod. Rep. 18, 231–281 (2001).

    Article  CAS  Google Scholar 

  49. Kohli, R. & Walsh, C. Enzymology of acyl chain macrocyclization in natural product biosynthesis. Chem. Commun. 297–307 (2003).

  50. Schwecke, T. et al. The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin. Proc. Natl Acad. Sci. USA 92, 7839–7843 (1995).

    Article  ADS  CAS  Google Scholar 

  51. Ahlert, J. et al. The calicheamycin gene cluster and its iterative type I enediyne PKS. Science 297, 1173–1176 (2002).

    Article  ADS  CAS  Google Scholar 

  52. Liu, W., Christensen, S. D., Standage, S. & Shen, B. Biosynthesis of the enediyne antitumor antibiotic C-1027. Science 297, 1170–1173 (2002).

    Article  ADS  CAS  Google Scholar 

  53. Shen, B., Liu, W. & Nonaka, K. Enediyne natural products: biosynthesis and prospects towards engineering novel antitumor agents. Curr. Med. Chem. 10, 2317–2325 (2003).

    Article  CAS  Google Scholar 

  54. Zerbe, K. et al. Crystal structure of OxyB, a cytochrome P450 implicated in an oxidative phenol coupling reaction during vancomycin biosynthesis. J. Biol. Chem. 277, 47476–47485 (2002).

    Article  CAS  Google Scholar 

  55. Pylypenko, O., Vitali, F., Zerbe, K., Robinson, J. A. & Schlichting, I. Crystal structure of OxyC, a cytochrome P450 implicated in an oxidative C–C coupling reaction during vancomycin biosynthesis. J. Biol. Chem. 278, 46727–46733 (2003).

    Article  CAS  Google Scholar 

  56. Walker, K. & Croteau, R. Taxol biosynthetic genes. Phytochemistry 58, 1–7 (2001).

    Article  CAS  Google Scholar 

  57. Chau, M., Jennewein, S., Walker, K. & Croteau, R. Taxol biosynthesis: molecular cloning and characterization of a cytochrome P450 taxoid 7 beta-hydroxylase. Chem. Biol. 11, 663–672 (2004).

    CAS  PubMed  Google Scholar 

  58. Jennewein, S., Long, R. M., Williams, R. M. & Croteau, R. Cytochrome p450 taxadiene 5 alpha-hydroxylase, a mechanistically unusual monooxygenase catalyzing the first oxygenation step of taxol biosynthesis. Chem. Biol. 11, 379–387 (2004).

    Article  CAS  Google Scholar 

  59. Yadav, G., Ghokale, R. S. & Mohanty, D. Computational approach for prediction of domain organization and substrate specificity of modular polyketide synthases. J. Mol. Biol. 328, 335–363 (2003).

    Article  CAS  Google Scholar 

  60. Eppelman, K., Stachelhaus, T. & Marahiel, M. A. Exploitation of the selectivity-conferring code of nonribosomal peptide synthetases for the rational design of novel peptide antibiotics. Biochemistry 42, 9718–9716 (2002).

    Article  Google Scholar 

  61. Lu, W., Leimkuhler, C., Oberthur, M., Kahne, D. & Walsh, C. AknK is an L-2-deoxyfucosyltransferase in the biosynthesis of the anthracycline aclacinomycin. Biochemistry 43, 4548–4558 (2004).

    Article  CAS  Google Scholar 

  62. Losey, H. C. et al. Incorporation of glucose analogs by glycosyltransferases GtfE and GtfD from the vancomycin biosynthetic pathway to generate variant glycopeptides. Chem. Biol. 9, 1305–1314 (2002).

    Article  CAS  Google Scholar 

  63. Mende, Z. C. & Salas, J. A. Altering the glycosylation pattern of bioactive compounds. Trends Biotechnol. 19, 449–456 (2001).

    Article  Google Scholar 

  64. McDaniel, R. et al. Multiple genetic modifications of the erythromycin gene cluster to produce a library of novel ‘unnatural’ natural products. Proc. Natl Acad. Sci. USA 96, 1846–1851 (1999).

    Article  ADS  CAS  Google Scholar 

  65. Tang, L. & McDaniel, R. Construction of desosamine containing polyketide libraries using a glycosyltransferase with broad substrate specificity. Chem. Biol. 8, 547–555 (2001).

    Article  CAS  Google Scholar 

  66. Wohlleben, W. & Pelzer, S. New compounds by combining modern genomics and old-fashioned mutasysnthesis. Chem. Biol. 9, 1163–1166 (2002).

    Article  CAS  Google Scholar 

  67. Huang, Q., Roessner, C. A., Croteau, R. & Scott, A. I. Engineering E. coli for the synthesis of taxadiene, a key intermediate in the biosynthesis of taxol. Biorg. Med. Chem. 9, 2237–2242 (2001).

    Article  CAS  Google Scholar 

  68. Martin, V. J., Pitera, D. J., Withers, S. T., Newman, J. D. & Keasling, J. D. Engineering a mevalonate pathway in E. coli for production of terpenoids. Nature Biotechnol. 21, 796–802 (2003).

    Article  CAS  Google Scholar 

  69. Ondeyka, J. G. et al. Nodulisporic acids C, C1, and C2: a series of D-ring-opened nodulisporic acids from the fungus Nodulisporium sp. J. Nat. Prod. 66, 121–124 (2003).

    Article  CAS  Google Scholar 

  70. Brady, S. F., Bondi, S. M. & Clardy, J. The guanacastepenes: a highly diverse family of secondary metabolites produced by an endophytic fungus. J. Am. Chem. Soc. 123, 9900–9901 (2001).

    Article  CAS  Google Scholar 

  71. Fuller, R. W. et al. A pentahalogenated monoterpene from the red alga Portieria hornemanni produces a novel cytotoxicity profile against a diverse panel of human tumor cell lines. J. Med. Chem. 35, 3007–3011 (1992).

    Article  CAS  Google Scholar 

  72. Piel, J. Metabolites from symbiotic bacteria. Nat. Prod. Rep. 21, 519–538 (2004).

    Article  CAS  Google Scholar 

  73. Luesch, H., Yoshida, W. Y., Moore, R. E., Paul, V. J. & Corbett, T. H. Total structure determination of apratoxin A, a potent novel cytotoxin from the marine cyanobacterium Lyngbya majuscula. J. Am. Chem. Soc. 123, 5418–5423 (2001).

    Article  CAS  Google Scholar 

  74. Edwards, D. J. et al. Structure and biosynthesis of the jamaicamides, new mixed polyketide-peptide neurotoxins from the marine cyanobacterium Lyngbya majuscula. Chem. Biol. 11, 817–833 (2004).

    Article  MathSciNet  CAS  Google Scholar 

  75. Gerth, K., Bedorf, N., Hofle, G., Irschik, H. & Reichenbach, H. Epothilons A and B: antifungal and cytotoxic compounds from Sorangium cellulosum (Myxobacteria). Production, physico-chemical and biological properties. J. Antibiot. (Tokyo) 49, 560–563 (1996).

    Article  CAS  Google Scholar 

  76. Sasse, F., Steinmetz, H., Heil, J., Hofle, G. & Reichenbach, H. Tubulysins, new cytostatic peptides from myxobacteria acting on microtubuli. Production, isolation, physico-chemical and biological properties. J. Antibiot. (Tokyo) 53, 879–885 (2000).

    Article  CAS  Google Scholar 

  77. Pace, N. R. A molecular view of microbial diversity and the biosphere. Science 276, 734–740 (1997).

    Article  CAS  Google Scholar 

  78. Kaeberlein, T., Lewis, K. & Epstein, S. S. Isolating ‘uncultivable’ microorganisms in pure culture in a simulated natural environment. Science 296, 1127–1129 (2002).

    Article  ADS  CAS  Google Scholar 

  79. Wang, G. Y. et al. Novel natural products from soil DNA libraries in a streptomycete host. Org. Lett. 2, 2401–2404 (2000).

    Article  CAS  Google Scholar 

  80. Brady, S., Chao, C. J. & Clardy, J. New natural product families from an eDNA cluster. J. Am. Chem. Soc. 124, 9968–9969 (2002).

    Article  CAS  Google Scholar 

  81. Zazopoulos, E. et al. A genomics-guided approach for discovering and expressing cryptic metabolic pathways. Nature Biotechnol. 21, 187–190 (2003).

    Article  CAS  Google Scholar 

  82. Jennewein, S., Wildung, M. R., Chau, M., Walker, K. & Croteau, R. Random sequencing of an induced Taxus cell cDNA library for identification of clones involved in Taxol biosynthesis. Proc. Natl Acad. Sci. USA 101, 9149–9154 (2004).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank G. J. Gatto and K. N. Maloney for their help in preparing this article.

Author information

Authors and Affiliations

  1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Jon Clardy & Christopher Walsh

Authors
  1. Jon Clardy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher Walsh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jon Clardy.

Ethics declarations

Competing interests

J. Clardy and C.Walsh advise several natural product-based companies including Eisai Research Institute, Novobiotics, Kosan Biosciences and Vicuron Pharmaceuticals.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Clardy, J., Walsh, C. Lessons from natural molecules. Nature 432, 829–837 (2004). https://doi.org/10.1038/nature03194

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03194

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing