Application of natural product-inspired diversity-oriented synthesis to drug discovery

  • Lisa A. Marcaurelle
  • Charles W. Johannes
Part of the Progress in Drug Research book series (PDR, volume 66)


Natural products have played a critical role in the identification of numerous medicines. Synthetic organic chemistry and combinatorial chemistry strategies such as diversity-oriented synthesis (DOS) have enabled the synthesis of natural product-like compounds. The combination of these approaches has both improved the desired biological properties of natural products as well as the identification of novel compounds. Diversity concepts and strategies to access novel compounds inspired by natural products will be reviewed.


Drug Discovery SHIKIMIC Acid Nicotine Agonist Allylic Alcohol Chemical Genetic 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Breinbauer R, Vetter IR, Waldmann H (2002) From protein domains to drug candidates — natural products as guiding principles in the design and synthesis of compound libraries. Angew Chem Int Ed 41: 2878–2890CrossRefGoogle Scholar
  2. 2.
    Newman DJ, Cragg GM, Snader KM (2003) Natural products as a source of new drugs over the period 1981–2002. J Nat Prod 66: 1002–1037CrossRefGoogle Scholar
  3. 3.
    Martin YC (2001) Diverse viewpoints on computational aspects of molecular diversity. J Comb Chem 3: 231–250PubMedCrossRefGoogle Scholar
  4. 4.
    Martin YC, Critchlow RE (1999) Beyond mere diversity: tailoring combinatorial libraries for drug discovery. J Comb Chem 1: 32–45PubMedCrossRefGoogle Scholar
  5. 5.
    Lipinski CA, Lombardo F, Dominy BW (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev 23: 3–25CrossRefGoogle Scholar
  6. 6.
    Tudor O, Hann M (2004) Pursuing the leadlikeness concept in pharmaceutical research. Curr Opin Chem Biol 8: 255–263CrossRefGoogle Scholar
  7. 7.
    Rishton G (2003) Non-leadlikeness and leadlikeness in biochemical screening. Drug Disc Today 8: 86–96CrossRefGoogle Scholar
  8. 8.
    Lee ML, Schneider G (2001) Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries. J Comb Chem 3: 284–289PubMedCrossRefGoogle Scholar
  9. 9.
    Dolan KA (2006) Amgen’s enemies. Forbes 30 September 2006Google Scholar
  10. 10.
    Haggarty S (2005) The principle of complementarity: chemical versus biological space. Curr Opin Chem Biol 9: 296–303PubMedCrossRefGoogle Scholar
  11. 11.
    Mickel SJ (2004) Toward a commercial synthesis of (+)-discodermolide. Curr Opin Drug Disc Dev 7: 869–881Google Scholar
  12. 12.
    Zheng W, Seletsky BM, Palme MH, Lydon PJ, Singer LA, Chase CE, Lemelin CA, Shen Y, Davis H, Tremblay L et al (2004) Macrocyclic ketone analogues of halichondrin B. Bioorg Med Chem Lett 14: 5551–5554PubMedCrossRefGoogle Scholar
  13. 13.
    Wilson R, Danishefsky SJ (2006) Small molecule natural products in the discovery of therapeutic agents: The synthesis connection. J Org Chem 71: 8329–8351PubMedCrossRefGoogle Scholar
  14. 14.
    Burke MD, Schreiber SL (2004) A planning strategy for diversity-oriented synthesis. Angew Chem Int Ed 43: 46–58CrossRefGoogle Scholar
  15. 15.
    Kumagai N, Muncipinto G, Schreiber SL (2006) Short synthesis of skeletally and stereochemically diverse small molecules by coupling Petasis condensation reactions to cyclization reactions. Angew Chem Int Ed 45: 3635–3638CrossRefGoogle Scholar
  16. 16.
    Wyatt EE, Fergus S, Gakkoway WRJD, Bender A, Fox DJ, Plowright AT, Jessiman AS, Welch M, Spring DR (2006) Skeletal diversity construction via a branching synthetic strategy. Chem Comm 3296–3298Google Scholar
  17. 17.
    Kim Y, Arai M, Arai T, Lamenzo J, Dean E, Patterson N, Clemons P, Schreiber SL (2004) Relationship of stereochemical and skeletal diversity of small molecules to cellular measurement space. J Am Chem Soc 126: 14740–14745PubMedCrossRefGoogle Scholar
  18. 18.
    Stockwell BR (2004) Exploring biology with small organic molecules. Nature 432: 846–854PubMedCrossRefGoogle Scholar
  19. 19.
    Stockwell BR (2000) Chemical genetics: Ligand-based discovery or gene function. Nature Rev Genetics 1: 116–125CrossRefGoogle Scholar
  20. 20.
    Koch MA, Schuffenhauer A, Scheck M, Wetzel S, Casaulta M, Odermatt A, Ertl P, Waldman H (2005) Charting biologically relevant chemical space: A structural classification of natural products. PNAS 12: 17272–17277CrossRefGoogle Scholar
  21. 21.
    Noren-Muller A, Reis-Correa Jr I, Prinz H, Rosenbaum C, Saxena K, Schwalbe HJ, Vestweber D, Cagna G, Schunk S, Schwarz O et al (2006) Discovery of protein phosphatase inhibitor classes by biology-oriented synthesis. PNAS 103: 10606–10611PubMedCrossRefGoogle Scholar
  22. 22.
    Decker F, Knoch M, Waldmann H (2005) Protein similarity structure clustering and natural product structure as inspiration sources for drug development and chemical genomics. Curr Opin Chem Biol 9: 232–239CrossRefGoogle Scholar
  23. 23.
    Boldt G, Dickerson T, Janda K (2006) Emerging chemical and biological approaches for the preparation of discovery libraries. Drug Disc Today 11: 143–148CrossRefGoogle Scholar
  24. 24.
    Feher M, Schmidt JM (2003) Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J Chem Inf Compu Sci 43: 218–227CrossRefGoogle Scholar
  25. 25.
    Ortholand J, Ganesan A (2004) Natural products and combinatorial chemistry: Back to the future. Curr Opin Chem Biol 8: 271–280PubMedCrossRefGoogle Scholar
  26. 26.
    Dobson CM (2004) Chemical space and biology. Nature 432: 824–828PubMedCrossRefGoogle Scholar
  27. 27.
    Fergus S, Bender A, Spring D (2005) Assessment of structural diversity in combinatorial synthesis. Curr Opin Chem Biol 9: 304–309PubMedCrossRefGoogle Scholar
  28. 28.
    Lipinski C, Hopkins A (2004) Navigating chemical space for biology and medicine. Nature 432: 855–861PubMedCrossRefGoogle Scholar
  29. 29.
    McGovern SL, Caselli E, Grigorieff, N, Shoichet BK (2002) A common mechanism underlying promiscuous inhibitors from virtual and highthroughput screening. J Med Chem 45: 1712–1722PubMedCrossRefGoogle Scholar
  30. 30.
    Ellis JR, Minto A (2003) Join the crowd. Nature 425: 27–28PubMedCrossRefGoogle Scholar
  31. 31.
    Ulaczyk-Lesanako A, Hall HG (2005) Wanted: new multicomponent reactions for generating libraries of polycyclic natural products. Curr Opin Chem Biol 9: 266–276CrossRefGoogle Scholar
  32. 32.
    Shang S, Tan DS (2005) Advancing chemistry and biology through diversity-oriented synthesis of natural product-like libraries. Curr Opin Chem Biol 9: 248–258PubMedCrossRefGoogle Scholar
  33. 33.
    Tan DS (2004) Current progress in natural product-like libraries for discovery screening. Comb Chem & High Throughput Screening 7: 631–643Google Scholar
  34. 34.
    Boldi AM (2004) Libraries from natural product-like scaffolds. Curr Opin Chem Biol 8: 282–286CrossRefGoogle Scholar
  35. 35.
    Cragg GM, Newman DJ, Snader KM (1997) Natural products in drug discovery and development. J Nat Prod 60: 52–60PubMedCrossRefGoogle Scholar
  36. 36.
    Clardy J, Walsh C (2004) Lessons from natural molecules. Nature 432: 829–837PubMedCrossRefGoogle Scholar
  37. 37.
    Arkin MR, Wells JA (2004) Small-molecule inhibitors of protein-protein interactions: progression towards the dream. Nat Rev Drug Discov 3: 301–317PubMedCrossRefGoogle Scholar
  38. 38.
    Firn RD, Jones CG (2003) Natural products — a simple model to explain chemical diversity. Nat Prod Rep 20: 382–391PubMedCrossRefGoogle Scholar
  39. 39.
    Muller G (2003) Medicinal chemistry of target family-directed masterkeys. Drug Disc Today 8: 681–691CrossRefGoogle Scholar
  40. 40.
    Pelish HE, Westwood NJ, Feng Y, Kirchhausen T, Shair MD (2001) 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: 6740–6741PubMedCrossRefGoogle Scholar
  41. 41.
    Goess BC, Hannoush RN, Chan LK, Kirchhausen T, Shair, MD (2006) Synthesis of a 10,000-membered library of molecules resembling carpanone and discovery of vesicular traffic inhibitors. J Am Chem Soc 128: 5391–5403PubMedCrossRefGoogle Scholar
  42. 42.
    Lo MMC, Neaumann CS, Nagayama S, Perlstein EO, Schreiber SL (2004) A library of spirooxindoles based on a stereoselective three-component coupling reaction. J Am Chem Soc 126: 16077–16086PubMedCrossRefGoogle Scholar
  43. 43.
    Zhang L, Caroll P, Meggers E (2003) Rutheium complexes as protein kinase inhibitors. Org Lett 6: 521–523CrossRefGoogle Scholar
  44. 44.
    Williams DS, Atilla GE, Bregman H, Arzoumanian A, Klein PS, Meggers E (2005) Switching on a signaling pathway with an organometallic ruthenium complex. Angew Chem Int Ed 44: 1984–1987CrossRefGoogle Scholar
  45. 45.
    Spring DR, Krishnan S, Blackwell HE, Schreiber SL (2002) Diversity-oriented synthesis of biaryl-containing medium rings using a one bead/one stock solution platform J Am Chem Soc 124: 1354–1363PubMedCrossRefGoogle Scholar
  46. 46.
    Krishnan S, Schreiber SL (2004) Syntheses of stereochemically diverse nine-membered ring-containing biaryls. Org Lett 6: 4021–4024PubMedCrossRefGoogle Scholar
  47. 47.
    Nefzi A, Ostresh JM, Yu J, Houghten RA (2004) Combinatorial chemistry: Libraries from libraries, the art of diversity-oriented transformation of resin-bound peptides and chiral polyamides to low molecular weight acyclic and heterocyclic compounds. J Org Chem 69: 3603–3609PubMedCrossRefGoogle Scholar
  48. 48.
    Nikolaou KC, Pfefferkorn JA, Barluena S, Mitchell HJ, Roecker AJ, Cao GQ (2000) Natural product-like combinatorial libraries based on privileged structures. 3. The ‘libraries from libraries’ principle for diversity enhancement of benzopyran libraries. J Am Chem Soc 122: 9968–9976CrossRefGoogle Scholar
  49. 49.
    Ko SK, Jang HJ, Kim E, Park SB (2006) Concise and diversity-oriented synthesis of novel scaffolds embedded with privileged benzopyran motif. Chem Comm 2962–2964Google Scholar
  50. 50.
    Lee D, Sello JK, Schreiber SL (1999) A strategy for macrocyclic ring closure and functionalization aimed toward split-pool syntheses. J Am Chem Soc 121: 10648–10649CrossRefGoogle Scholar
  51. 51.
    Su Q, Beeler AB, Lobkovsky E, Porco HA, Panek JS (2003) Stereochemical diversity through cyclodimerization: Synthesis of polyketide-like macrodiolides. Org Lett 5: 2149–2152PubMedCrossRefGoogle Scholar
  52. 52.
    Schmidt DR, Kwon O, Schreiber SL (2004) Macrolactones in diversity-oriented synthesis: Preparation of a pilot library and exploration of factors controlling macrocylization. J Comb Chem 6: 286–292PubMedCrossRefGoogle Scholar
  53. 53.
    Tan DS, Foley MA, Shair MD, Schreiber SL (1998) Stereoselective synthesis of over two million compounds having structural features both reminiscent of natural products and compatible with miniaturized cell-based assays. J Am Chem Soc 120: 8565–8566CrossRefGoogle Scholar
  54. 54.
    Tan DS, Foley MA, Stockwell BR, Shair MD, Schreiber SL (1999) Synthesis and preliminary evaluation of a library of polycyclic small molecules for use in chemical genetic assays. J Am Chem Soc 121: 9073–9087CrossRefGoogle Scholar
  55. 55.
    Mitchell JM, Shaw JT (2006) A structurally diverse library of polycyclic lactams resulting from systematic placement of proximal functional groups. Angew Chem Int Ed 45: 1722–1726CrossRefGoogle Scholar
  56. 56.
    Su S, Acquilano DE, Arumugasamy J, Beeler AB, Eastwood EL, Giguere JR, Lan P, Lei X, Min GK, Yeaau]ger AR et al (2005) Convergent synthesis of a complex oxime library using chemical domain shuffling Org Lett 7: 2751–2754PubMedCrossRefGoogle Scholar
  57. 57.
    Beeler AB, Schaus SE, Porco Jr J (2005) A chemical library synthesis using convergent approaches. Curr Opin Chem Biol 9: 277–284PubMedCrossRefGoogle Scholar
  58. 58.
    Tsoi CJ, Khosla C (1995) Combinatorial biosynthesis of ‘unnatural’ natural products: the polyketides example. Chem Biol 2: 355–362PubMedCrossRefGoogle Scholar
  59. 59.
    Spiegel DA, Schroeder FC, Duvall JR, Schreiber SL (2006) An oligomer-based approach to skeletal diversity in small-molecule synthesis. J Am Chem Soc 128: 14766–14767PubMedCrossRefGoogle Scholar
  60. 60.
    Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev 23: 3–25CrossRefGoogle Scholar
  61. 61.
    Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45: 2615–2623PubMedCrossRefGoogle Scholar
  62. 62.
    Tallarico JA, Depew KM, Pelish HE, Westwood NJ, Lindsley CW, Shair MD, Schrieber SL, Foley MA (2001) An alkylsilyl-tethered, high-capacity solid support amenable to diversity-oriented synthesis for one bead, one stock solution chemical genetics. J Comb Chem 3: 312–318PubMedCrossRefGoogle Scholar
  63. 63.
    Castro AC, Deng W, Depew KM, Foley MA, Fritz CC, Georges Evangelinos AT, Grogan MJ, Hafeez N, Holson EB, Hopkins BT et al (2006) Compounds and methods for inhibiting the interaction of Bcl proteins with binding partners. PCT Int. Appl. 331 pp. WO 2006009869Google Scholar
  64. 64.
    Reibarkh M, Malia TJ, Wagner G (2006) Identification of individual protein-ligand NOEs in the limit of intermediate exchange. J Biomol NMR 36: 1–11PubMedCrossRefGoogle Scholar
  65. 65.
    Christensen BG, Foley MA, Georges Evangelinos AT, Lui T, Porter JR, Ripka AS, Zhang L (2006) Isoxazolidine compounds for treatment of bacterial infections. PCT Int. Appl. WO 2006009907Google Scholar
  66. 66.
    Cory S, Adams JM (2002) The Bcl2 family: regulators of the cellular life-or-death switch. Nature Rev Cancer 2: 647–656CrossRefGoogle Scholar
  67. 67.
    Arkin M (2005) Protein-protein interactions in cancer: small molecules going in for the kill. Curr Opin Chem Biol 9: 317–324PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag, Basel (Switzerland) 2008

Authors and Affiliations

  • Lisa A. Marcaurelle
    • 1
  • Charles W. Johannes
    • 2
  1. 1.Broad Institute of Harvard and MITCambridgeUSA
  2. 2.Infinity Pharmaceuticals, Inc.CambridgeUSA

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