Advertisement

Natural Products as Sources of Anticancer Agents: Current Approaches and Perspectives

  • Gordon M. Cragg
  • David J. Newman
Chapter

Abstract

Natural products from marine invertebrates and microbes from terrestrial (and marine) sources together with higher plants have been an important source of many clinically useful anticancer agents. Over 60% of the current anticancer drugs have their origin in one way or another from natural sources. Some important examples include the vinca alkaloids, camptothecin derivatives, and taxanes. This chapter will briefly cover older agents where new findings have been published but will emphasize current promising new agents which are in clinical use and development, based on activity against cancer-related targets. These compounds may have been developed from targeted or phenotypic screening programs, and examples will be given from each approach. Then the importance of multidisciplinary collaboration in the generation and optimization of novel molecular leads from natural product sources will be discussed, with examples chosen to demonstrate how chemical and biochemical strategies were used to improve their biological effects.

Keywords

Natural products Biodiversity Anticancer agents Multidisciplinary collaboration 

References

  1. Agatsuma T (2017) Development of new ADC technology with topoisomerase I inhibitor. Yakugaku Zasshi 137:545–550CrossRefPubMedGoogle Scholar
  2. Andrejauskas-Buchdunger E, Reganass U (1992) Differential inhibition of the epidermal growth factor-, platelet derived growth factor-, and protein kinase C-mediated signal transduction pathways by the staurosporine derivative CGP 41251. Cancer Res 52:5353–5358PubMedPubMedCentralGoogle Scholar
  3. Awada A, Bondarenko IN, Bonneterre J et al (2014) A randomized controlled phase II trial of a novel composition of paclitaxel embedded into neutral and cationic lipids targeting tumor endothelial cells in advanced triple-negative breast cancer (TNBC). Ann Oncol 25:824–831CrossRefPubMedGoogle Scholar
  4. Basmadjian C, Zhao Q, Djehal A et al (2014) Cancer wars: natural products strike back. Front Chem 2:20CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bebbington MWP (2017) Natural product analogues: towards a blueprint for analogue-focused synthesis. Chem Soc Rev 46:5059–5109CrossRefPubMedGoogle Scholar
  6. Bertin MJ, Schwartz SL, Lee J et al (2015) Spongosine production by a Vibrio harveyi strain associated with the sponge Tectitethya crypta. J Nat Prod 78:493–499CrossRefPubMedPubMedCentralGoogle Scholar
  7. Black J, Menderes G, Bellone S et al (2016) SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows antitumor activity in uterine serous carcinoma with HER2/Neu expression. Mol Cancer Ther 15:1900–1909CrossRefPubMedGoogle Scholar
  8. Chan SY, Gordon AN, Coleman RE et al (2003) A phase 2 study of the cytotoxic immunoconjugate CMB-401 (hCTM01-calicheamicin) in patients with platinum-sensitive recurrent epithelial ovarian carcinoma. Cancer Immunol Immunother 52:243–248PubMedGoogle Scholar
  9. Cragg GM, Newman DJ (2014) Natural products as sources of new anticancer agents. In: Feliciano AS, Filho VC (eds) Descoberta, Desenho e Desenvolvivmento de Novos Agentes Anticancer no Ambito do Programa Iberoamericano CYTED. Editoria Univali, Itajai, pp 67–118Google Scholar
  10. Cragg GM, Pezzuto JM (2016) Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med Princ Pract 25:41–59CrossRefPubMedGoogle Scholar
  11. Damelin M, Bankovich A, Park A et al (2015) Anti-EFNA4 calicheamicin conjugates effectively target triple-negative breast and ovarian tumor-initiating cells to result in sustained tumor regressions. Clin Cancer Res 21:4165–4173CrossRefPubMedGoogle Scholar
  12. Davis AM, Tinker AV, Friedlander M (2014) “Platinum resistant” ovarian cancer: what is it, who to treat and how to measure benefit? Gynecol Oncol 133:624–631CrossRefPubMedGoogle Scholar
  13. Elgersma RC, Coumans RG, Huijbregts T et al (2015) Design, synthesis, and evaluation of linker-duocarmycin payloads: toward selection of HER2-targeting antibody-drug conjugate SYD985. Mol Pharm 12:1813–1835CrossRefPubMedGoogle Scholar
  14. Galal A, El-Bakly WM, El-Demedash E (2016) Selective A3 adenosine receptor agonist protects against doxorubicin-induced cardiotoxicity. Cancer Chemother Pharmacol 77:309–322CrossRefPubMedGoogle Scholar
  15. Giddings LA, Newman DJ (2015) Bioactive compounds from extremophiles, genomic studies, biosynthetic gene clusters, and new dereplication methods. In: Tiquia-Arashiro SM, Mormile M (eds) Extremophilic bacteria, Springer briefs in microbiology. Springer, Heidelberg, pp 1–58Google Scholar
  16. Giddings LA, Newman DJ (2017) Microbial involvement in the production of natural products by plants, marine invertebrates and other organisms. In: Atta-ur-Rahman (ed) Frontiers in natural product chemistry, vol 3. Bentham, Karachi, pp 1–64Google Scholar
  17. Gottfried K, Klar U, Platzek J et al (2015) Biocatalysis at work: applications in the development of Sagopilone. ChemMedChem 10:1240–1248CrossRefPubMedGoogle Scholar
  18. Graybill WS, Coleman RL (2016) Folate receptor-targeted therapeutics for ovarian cancer. Drugs Future 41:137–143CrossRefGoogle Scholar
  19. Herzog TJ, Kutarska E, Bidzińsk M et al (2016) Adverse event profile by folate receptor status for vintafolide and pegylated liposomal doxorubicin in combination, versus pegylated liposomal doxorubicin alone, in platinum-resistant ovarian cancer: Exploratory analysis of the Phase II PRECEDENT trial. Int J Gynecol Cancer 26:1580–1585CrossRefPubMedPubMedCentralGoogle Scholar
  20. Huang M, Gao H, Chen Y et al (2007) Chimmitecan, a novel 9-substituted camptothecin, with improved anticancer pharmacologic profiles in vitro and in vivo. Clin Cancer Res 13:1298–1307CrossRefPubMedGoogle Scholar
  21. Huang G, Wang H, Yang LX (2010) Enhancement of radiation-induced DNA damage and inhibition of its repair by a novel camptothecin analog. Anticancer Res 30:937–944PubMedGoogle Scholar
  22. Joerger M, Hess D, Delmonte A et al (2015) Integrative population pharmacokinetic and pharmacodynamic dose finding approach of the new camptothecin compound namitecan (ST1968). Br J Clin Pharmacol 80:128–138CrossRefPubMedPubMedCentralGoogle Scholar
  23. Jones RP, Malik HZ, Fenwick SW et al (2016) PARAGON II – a single arm multicentre phase II study of neoadjuvant therapy using irinotecan bead in patients with resectable liver metastases from colorectal cancer. Eur J Surg Oncol 42:1866–1872CrossRefPubMedGoogle Scholar
  24. Kusari S, Lamsho M, Kusari P et al (2014) Endophytes are hidden producers of maytansine in Putterlickia roots. J Nat Prod 77:2577–2584CrossRefPubMedGoogle Scholar
  25. Kusari P, Kusari S, Eckelmann D et al (2016) Cross-species biosynthesis of maytansine in Maytenus serrata. RSC Adv 6:10011–10016CrossRefGoogle Scholar
  26. Lambert JM (2012) Drug-conjugated antibodies for the treatment of cancer. Br J Clin Pharmacol 76:248–262CrossRefPubMedCentralGoogle Scholar
  27. Lee KW, Lee KH, Zang DY et al (2015) Phase I/II study of weekly Oraxol for the second-line treatment of patients with metastatic or recurrent gastric cancer. Oncologist 20(8):896–897CrossRefPubMedPubMedCentralGoogle Scholar
  28. Li JY, Perry SR, Muniz-Medina V et al (2016) A biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell 29(1):117–129CrossRefPubMedGoogle Scholar
  29. Liu X, Kantarjian H, Plunkett W (2012) Sapacitabine for cancer. Expert Opin Investig Drugs 21(4):541–555CrossRefPubMedPubMedCentralGoogle Scholar
  30. Mantaj J, Jackson PJM, Rahman KM et al (2017) From anthramycin to pyrrolobenzodiazepine (PBD) containing antibody-drug conjugates (ADCs). Angew Chem Int Ed Engl 56(2):462–488CrossRefPubMedGoogle Scholar
  31. Martín MJ, Coello L, Fernández R et al (2013) Isolation and first total synthesis of PM050489 and PM060184, two new marine anticancer compounds. J Am Chem Soc 135(27):10164–10171CrossRefPubMedGoogle Scholar
  32. Montalban-Bravo G, Garcia-Manero G (2015) Novel drugs for older patients with acute myeloid leukemia. Leukemia 29(4):760–769CrossRefPubMedGoogle Scholar
  33. Nakada T, Masuda T, Naito H et al (2016) Novel antibody drug conjugates containing exatecan derivative-based cytotoxic payloads. Bioorg Med Chem Lett 26:1542–1545CrossRefPubMedGoogle Scholar
  34. Newman DJ (2008) Natural products as leads to potential drugs: An old process or the new hope for drug discovery? J Med Chem 51:2589–2599CrossRefPubMedGoogle Scholar
  35. Newman DJ (2016) Predominately uncultured microbes as sources of bioactive agents. Front Microbiol 7:1832CrossRefPubMedPubMedCentralGoogle Scholar
  36. Newman DJ (2017) Recent advances in screening and identification of novel biologically active natural compounds. F1000 Fac Rev 6:783CrossRefGoogle Scholar
  37. Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75(3):311–335CrossRefPubMedPubMedCentralGoogle Scholar
  38. Newman DJ, Cragg GM (2014) Making sense of structures by utilizing Mother Nature’s chemical libraries as leads to potential drugs. In: Osbourn A, Goss RJ (eds) Natural products: discourse, diversity and design. Wiley, New York, pp 397–411CrossRefGoogle Scholar
  39. Newman DJ, Cragg GM (2015) Endophytic and epiphytic microbes as “sources” of bioactive agents. Front Chem 3:34CrossRefPubMedPubMedCentralGoogle Scholar
  40. Newman DJ, Cragg GM (2016a) Natural product scaffolds of value in medicinal chemistry. In: Brase S (ed) Privileged scaffolds in medicinal chemistry. Royal Society of Chemistry, London, pp 348–378Google Scholar
  41. Newman DJ, Cragg GM (2016b) Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79(3):629–661CrossRefPubMedGoogle Scholar
  42. Newman DJ, Cragg GM (2017) Current status of marine-derived compounds as warheads in anti-tumor drug candidates. Mar Drugs 15(4) 99.CrossRefPubMedCentralGoogle Scholar
  43. Newman DJ, Cragg GM, Snader KM (2000) The influence of natural products upon drug discovery. Nat Prod Rep 17(3):215–234CrossRefPubMedGoogle Scholar
  44. Newman DJ, Cragg GM, Kingston DGI (2015) Natural products as pharmaceuticals and sources for lead structures. In: Aldous D, Rognan D, Raboisson P et al (eds) The practice of medicinal chemistry, 4th edn. Elsevier, Amsterdam, pp 102–138Google Scholar
  45. Pera B, Barasoain I, Pantazopoulou A et al (2013) New interfacial microtubule inhibitors of marine origin, PM050489/PM060184, with potent antitumor activity and a distinct mechanism. ACS Chem Biol 8(9):2084–2094CrossRefPubMedGoogle Scholar
  46. Santamaría NG, Robles CM, Giraudon C et al (2016) Lurbinectedin specifically triggers the degradation of phosphorylated RNA polymerase II and the formation of DNA breaks in cancer cells. Mol Cancer Ther 15(10):2399–2412CrossRefGoogle Scholar
  47. Shi J, Kantoff PW, Wooster R et al (2017) Cancer nanomedicine: Progress, challenges and opportunities. Nat Rev Cancer 17(1):20–37CrossRefPubMedGoogle Scholar
  48. Wakimoto T, Egami Y, Nakashima Y et al (2014) Calyculin biogenesis from a pyrophosphate protoxin produced by a sponge symbiont. Nat Chem Biol 10(8):648–655CrossRefPubMedGoogle Scholar
  49. Wicki A, Ritschard R, Loesch U et al (2015) Large-scale manufacturing of GMP-compliant anti-EGFR targeted nanocarriers: Production of doxorubicin-loaded ant-EGFR-immunoliposomes for a first-in-man clinical trial. Int J Pharm 484(1–2):8–15CrossRefPubMedGoogle Scholar
  50. Wilson MC, Mori T, Ruckert C et al (2014) An environmental bacterial taxon with a large and distinct metabolic repertoire. Nature 506(7486):58–62CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Gordon M. Cragg
    • 1
  • David J. Newman
    • 2
  1. 1.GaithersburgUSA
  2. 2.WayneUSA

Personalised recommendations