Abstract
Over 60% of the current anticancer drugs have their origin in one way or another from natural sources. Nature continues to be the most prolific source of biologically active and diverse chemotypes, and it is becoming increasingly evident that associated microbes may often be the source of biologically active compounds originally isolated from host macro-organisms. While relatively few of the actual isolated compounds advance to become clinically effective drugs in their own right, these unique molecules may serve as models for the preparation of more efficacious analogs using chemical methodology such as total or combinatorial (parallel) synthesis, or manipulation of biosynthetic pathways. In addition, conjugation of toxic natural molecules to monoclonal antibodies or polymeric carriers specifically targeted to epitopes on tumors of interest can lead to the development of efficacious targeted therapies. The essential role played by natural products in the discovery and development of effective anticancer agents, and the importance of multidisciplinary collaboration in the generation and optimization of novel molecular leads from natural product sources is reviewed.
Similar content being viewed by others
References
Abe F, Horikoshi K (2001) The biotechnological potential of piezophiles. Trends Biotechnol 19:102–108
Agoulnik S, Kuznetsov G, Tendyke K et al (2005) Sensitivity to halichondrin analog E7389 and hemiasterlin analog E7974 correlates with beta III tubulin isotype expression in human breast cancer cell lines. In: 41st Annual Meeting of American Society of Clinical Oncology (ASCO), Abstract 2012
Alhamadsheh MM, Hudson RA, Tillekeratne LMV (2006) Design, total synthesis, and evaluation of novel open-chain epothilone analogues. Org Lett 8:685–688
Altmann K-H (2005) Recent developments in the chemical biology of epothilones. Curr Pharm Des 11:1595–1613
Amna T, Puri SC, Verma V et al (2006) Bioreactor studies on the endophytic fungus Entrophospora infrequens for the production of an anticancer alkaloid camptothecin. Can J Microbiol 52:189–196
Andersen RJ, Roberge M (2005) HTI-286, a synthetic analog of the antimitotic natural product hemiasterlin. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 267–280
Arcamone F (2005) Anthracyclines. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 299–320
Bai R, Pettit GR, Hamel E (1990) Dolastatin 10, a powerful cytostatic peptide derived from a marine animal: inhibition of tubulin polymerization mediated through the vinca alkaloid binding domain. Biochem Pharmacol 39:1941–1949
Banskota AH, McAlpine JB, Sørensen D et al (2006) Genomic analyses lead to novel secondary metabolites. Part 3. ECO-0501, a novel antibacterial of a new class. J Antibiot 59:533–542
Bode HB, Muller R (2005) The impact of bacterial genomics on natural product research. Angew Chem Int Ed 44:6828–6846
Bok JW, Hoffmeister D, Maggio-Hall LA et al (2006) Genomic mining for Aspergillus natural products. Chem Biol 13:31–37
Borman S (2003) The many faces of combinatorial chemistry. Chem Eng News 81(43):45–56
Borman S (2004) Rescuing combichem. Chem Eng News 82(40):32–40
Byrd JC, Peterson BL, Gabrilove J, Odenike et al (2005) Treatment of relapsed chronic lymphocytic leukemia by 72-hour continuous infusion or 1-hour bolus infusion of flavopiridol: results from cancer and leukemia group B study 19805. Clin Cancer Res 11:4176
Cachoux F, Isarno T, Wartmann M et al (2005) Scaffolds for microtubule inhibition through extensive modification of the epothilone template. Angew Chem Int Ed 44:7469–7473
Cassady JM, Chan KK, Floss HG et al (2004) Recent developments in the maytansinoid antitumor agents. Chem Pharm Bull (Tokyo) 52:1–26
Cavicchioli R, Siddiqui KS, Andrews D et al (2002) Low-temperature extremophiles and their applications. Curr Opin Biotechnol 13:253–261
Chang YT, Gray NS, Rosania GR et al (1999) Synthesis and application of functionally diverse 2, 6, 9-trisubstituted purine libraries as CDK inhibitors. Chem Biol 6:361–375
Clardy J, Walsh CT (2004) Lessons from natural molecules. Nature 432:829–837
Clardy J, Fischbach MA, Walsh CT (2006) New antibiotics from bacterial natural products. Nature Biotechnol 24:1541–1550
Class S (2002) Pharma overview. Chem Eng News 80(48):39–49
Cortes JE, Pazdur R (1995) Docetaxel. J Clin Oncol 13:2643–2655
Cragg GM, Newman DJ (2004) A tale of two tumor targets: topoisomerase I and tubulin. The Wall and Wani contribution to cancer chemotherapy. J Nat Prod 67:232–244
Cunningham C, Appleman LJ, Kirvan-Visovatti M et al (2005) Phase I and pharmacokinetic study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 11:7825–7833
de Jonge M, Verweiji J (2005) The epothilone dilemma. J Clin Oncol 23:9048–9050
Denmeade SR, Jakobsen CM, Janssen S et al (2003) Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer. J Nat Cancer Inst 95:990–1000
Duncan R (1997) Drug targeting: where are we now and where are we going? J Drug Target 5:1–4
Ebbinghaus S, Rubin E, Hersh E et al (2005) A phase I study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously daily for 5 consecutive days every 3 weeks in patients with advanced solid tumors. Clin Cancer Res 11:7807–7816
Engert A, Sausville EA, Vitetta E (1998) The emerging role of ricin A-chain immunotoxins in leukemia and lymphoma. Curr Top Microbiol Immunol 234:13–33
Evert S (2008) Peptide-producing powerhouses. Chem Eng News 86(43):48–50
Eyberger AL, Dondapati R, Porter JR (2006) Endophyte fungal isolates from Podophyllum peltatum produce podophyllotoxin. J Nat Prod 69:1121–1124
Ezra D, Castillo UF, Strobel GA et al (2004) Coronamycins, peptide antibiotics produced by a verticillate Streptomyces sp. (MSU 2110) endophytic on monstera sp. Microbiology 150:785–793
Feling RH, Buchanan GO, Mincer TJ et al (2003) Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed 42:355–357
Fieseler L, Hentschel U, Grozdanov L et al (2007) Widespread occurrence and genomic context of unusually small polyketide synthase genes in microbial consortia associated with marine sponges. J Appl Environ Microbiol 73:2144–2155
Flahive E, Srirangam J (2005) The dolastatins: novel antitumor agents from Dolabella auricularia. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 191–214
Gomes J, Steiner W (2004) Extremophiles and extremozymes. Food Technol Biotechnol 42:223–235
Gontang EA, Fenical W, Jensen PR (2007) Phylogenetic diversity of gram-positive bacteria cultured from marine sediments. Appl Environ Microbiol 73:3272–3282
Gueritte F, Fahy J (2005) The vinca alkaloids. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 123–136
Gunatilaka AAL (2006) Natural products from plant-associated microorganisms: distribution, structural diversity, bioactivity, and implications of their occurrence. J Nat Prod 69:509–526
Hale KJ, Hummersone MG, Manaviazar S et al (2002) The chemistry and biology of the bryostatin antitumour macrolides. Nat Prod Rep 19:413–453
Hecht SM (2005) Bleomycin group antitumor agents. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 357–382
Henríquez R, Faircloth G, Cuevas C (2005) Ecteinascidin 743 (ET-743, Yondelis), aplidin, and kahalalide F. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 215–240
Herbst RS, Hammond LA, Carbone DP et al (2003) A phase I/IIA trial of continuous five-day infusion of squalamine lactate (MSI-1256F) plus carboplatin and paclitaxel in patients with advanced non-small cell lung cancer. Clin Cancer Res 9:4108–4115
Hoffmeister D, Keller NP (2007) Natural products of filamentous fungi: enzymes, genes, and their regulation. Nat Prod Rep 24:393–416
Höfle G, Reichenbach H (2005) Epothilone, a myxobacterial metabolite with promising antitumor activity. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 413–450
Hoyoux A, Blaise V, Collins T et al (2004) Extreme catalysts from low-temperature environments. Biosci Bioeng 98:317–330
Itokawa H, Wang X, Lee K-H (2005) Homoharringtonine and related compounds. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 47–70
Janssen S, Rosen DM, Ricklis RM et al (2006) Pharmacokinetics, biodistribution and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug. Prostate 66:358–368
Johnson DB, Hallberg KB (2003) The microbiology of acidic mine waters. Res Microbiol 154:466–473
Khosla C (2000) Natural product biosynthesis: a new interface between enzymology and medicine. J Org Chem 65:8127–8133
Kingston DGI (2005) Taxol and its analogs. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 89–122
Kwon HC, Kauffman CA, Jensen PR et al (2006) Marinomycins A-D, antitumor-antibiotics of a new structure class from a marine actinomycete of the recently discovered genus “marinispora”. J Am Chem Soc 128:1622–1632
Lam KS (2007) New aspects of natural products in drug discovery. Trends Microbiol 15:279–289
Lee K-H, Xiao Z (2005) Podophyllotoxins and analogs. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 71–88
Li Q, Sham HL (2002) Discovery and development of antimitotic agents that inhibit tubulin polymerisation for the treatment of cancer expert. Opin Ther Pat 12:1663–1701
McAlpine JB, Bachmann BO, Piraee M et al (2005) Microbial genomics as a guide to drug discovery and structural elucidation: ECO-02301, a novel antifungal agent as an example. J Nat Prod 68:493–496
Meijer L, Raymond E (2003) Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials. Acc Chem Res 36:417–425
Melnikova I (2005) Wet age-related macular degeneration. Nat Rev Drug Discov 4:711–712
Moore KS, Wehrli S, Roder H et al (1993) Squalamine: an aminosterol antibiotic from the shark. Proc Natl Acad Sci USA 90:1354–1358
Mutter R, Wills M (2000) Chemistry and clinical biology of the bryostatins. Bioorg Med Chem 8:1841–1860
Newman DJ (2005) The bryostatins. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 137–150
Newman DJ, Cragg GM (2004) Marine natural products and related compounds in clinical and advanced preclinical trials. J Nat Prod 67:1216–1238
Newman DJ, Cragg GM (2005) The discovery of anticancer drugs from natural sources. In: Zhang L, Fleming GA, Demain AL (eds) Natural products: drug discovery. Therapeutics, and preventative medicine. Dekker, New York, pp 129–168
Newman DJ, Cragg GM (2007) Natural products as sources of new drugs over the last 25 years. J Nat Prod 70:1022–1037
Nicolaou KC, Vourloumis D, Winssinger N et al (2000) The art and science of total synthesis at the dawn of the twenty-first century. Angew Chem Int Ed 39:44–122
Norcross RD, Patterson I (1995) Total synthesis of bioactive marine macrolides. Chem Rev 95:2041–2114
Oh DC, Strangman WK, Kauffman CA et al (2007) Thalassospiramides A and B, immunosuppressive peptides from the marine bacterium Thalassospira sp. Org Lett 9:1525–1528
Partida-Martinez LP, Hertweck C (2005) Pathogenic fungus harbours endosymbiotic bacteria for toxin production. Nature 437:884–888
Pennati M, Capmpbell AJ, Curto M et al (2005) Potentiation of paclitaxel-induced apoptosis by the novel cyclin-dependent kinase inhibitor NU6140: a possible role for survivin down-regulation. Mol Cancer Ther 4:1328–1337
Persidis A (1998) Extremophiles. Nature Biotechnol 16:593–594
Piel J (2004) Metabolites from symbiotic bacteria. Nat Prod Rep 21:519–538
Piel J (2006) Bacterial symbionts: prospects for the sustainable production of invertebrate-derived pharmaceuticals. Curr Med Chem 13:39–50
Piel J, Hofer I, Hui D (2004a) Evidence for a symbiosis island involved in horizontal acquisition of pederin biosynthetic capabilities by the bacterial symbiont of Paederus fuscipes beetles. J Bacteriol 186:1280–1286
Piel J, Hui D, Wen G et al (2004b) Antitumor polyketide biosynthesis by an uncultivated bacterial symbiont of the marine sponge Theonella swinhoei. Proc Natl Acad SciUSA 101:16222–16227
Piel J, Butzke D, Fusetani N et al (2005) Exploring the chemistry of uncultivated bacterial symbionts: antitumor polyketides of the pederin family. J Nat Prod 68:472–479
Pinney KG, Jelinek C, Edvardsen K (2005) The discovery and development of the combretastatins. In: Cragg GM, Kingston DGI, Newman DJ et al (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 23–46
Puri SC, Verma V, Amna T et al (2005) An endophytic fungus from Nothapodytes foetida that produces camptothecin. J Nat Prod 68:1717–1719
Rachid S, Gerth K, Kochems I et al (2007) Deciphering regulatory mechanisms for secondary metabolite production in the myxobacterium Sorangium cellulosum So ce56. Mol Microbiol 63:1783–1796
Rademaker-Lakhai JM, Horenblas S, Meinhardt W et al (2005) Phase I clinical and pharmokinetic study of kahalalide F in patients with advanced androgen refractory prostate cancer. Clin Cancer Res 11:1854–1862
Rahier NJ, Thomas CJ, Hecht SM (2005) Camptothecin and its analogs. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 5–22
Rasila KK, Verschraegen C (2005) Tasidotin HCI. Curr Opin Investig Drugs 6:631–638
Rondon MR, August PR, Bettermann AD et al (2000) Cloning the soil metagenome: a strategy for accessing the genetic and functional diversity of uncultured microorganisms. Appl Environ Microbiol 66:2541–2547
Rose V, Schiller J, Wood A et al (2004) Randomized phase II trial of weekly squalamine, carboplatin, and paclitaxel as first line therapy for advanced non-small cell lung cancer. J Clin Oncol 22: 7109 (Meeting Abstracts)
Rossi M, Ciaramella M, Cannio R et al (2003) Extremophiles 2002. J Bacteriol 185:3683–3689
Salazar R, Casado E, Lopez Martin JA et al (2005) Clinical and pharmacokinetic phase I dose-finding study of kahalalide F (KF) administered as a prolonged infusion in patients with solid tumors. J Clin Oncol 23(16S): Abstract 2059
Sausville EA, Zaharevitz D, Gussio R et al (1999) Cyclin-dependent kinases: initial approaches to exploit a novel therapeutic target. Pharmacol Ther 82:285–292
Schiraldi C, De Rosa M (2002) The production of biocatalysts and biomolecules from extremophiles. Trends Biotechnol 20:515–521
Shimoyama T, Hamano T, Natsume T et al (2006) Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (soblidotin), in vitro. Pharmacogenom J 6:388–396
Short PL (2007) New Zealand plays to its strengths. Chem Eng News 85(4):20–21
Sills AK Jr, Williams JI, Tyler BM et al (1998) Squalamine inhibits angiogenesis and solid tumor growth in vivo and perturbs embryonic vasculature. Cancer Res 58:2784–2792
Sohoel H, Jensen AM, Moller JV et al (2006) Natural products as starting materials for development of second-generation SERCA inhibitors targeted towards prostate cancer cells. Bioorg Med Chem 14:2810–2815
Staunton J, Weissman KJ (2001) Polyketide biosynthesis: a millennium review. Nat Prod Rep 18:380–416
Stierle AE, Stierle DB, Patacinni B (2008) The berkeleyamides, amides from the acid lake fungus Penicillium rubrum. J Nat Prod 71(5):856–860
Strobel GA, Daisy B, Castillo U et al (2004) Natural products from endophytic microorganisms. J Nat Prod 67:257–268
Sudek S, Lopanik NB, Waggoner LE et al (2007) Identification of the putative polyketide gene cluster from the uncultivated microbial symbiont, Candidatus Endobugula sertula, of the marine bryozoan, Bugula neritina. J Nat Prod 70:67–74
Tan RX, Zou WX (2001) Endophytes: a rich source of functional metabolites. Nat Prod Rep 18:448–459
Tang L, Chung L, Carney JR et al (2005) Generation of new epothilones by genetic engineering of a polyketide synthase in Myxococcus xanthus. J Antibiot 58:178–184
Thomas MG, Bixby KA, Shen B (2005) Combinatorial biosynthesis of anticancer natural products. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 519–552
Udwary DW, Zeigler L, Asolkar RN et al (2007) Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proc Natl Acad Sci USA 104:10376–10381
Van de Weghe P, Eustache J (2005) The application of olefin metathesis to the synthesis of biologically active macrocyclic agents. Curr Top Med Chem 5:1495–1519
van den Burg B (2003) Extremophiles as a source for novel enzymes. Curr Opin Microbiol 6:213–218
Venter JC, Remington K, Heidelberg JF et al (2004) Environmental genome shotgun sequencing of the Sargasso Sea. Science 304:66–74
Walsh CT (2004) Polyketide and nonribosomal peptide antibiotics: modularity and versatility. Science 303:1805–1810
Walsh CT (2007) The chemical versatility of natural-product assembly lines. Acc Chem Res 41:4–10
Warnecke F, Luginbühl P, Ivanova N et al (2007) Metagenomic and functional analysis of hindgut microbiota of a wood-feeding higher termite. Nature 450:560–565
Wender PA, Lippa B (2000) Synthesis and biological evaluation of bryostatin analogues: the role of the A-ring. Tetrahedron Lett 41:1007–1011
Wender PA, De Brabander J, Harran PG et al (1998a) Synthesis of the first members of a new class of biologically active bryostatin analogues. J Am Chem Soc 120:4534–4535
Wender PA, De Brabander J, Harran PG et al (1998b) The design, computer modeling, solution structure, and biological evaluation of synthetic analogs of bryostatin 1. Proc Natl Acad Sci USA 95:6624–6629
Wender PA, Hinkle KW, Koehler MFT et al (1999) The rational design of potential chemotherapeutic agents: synthesis of bryostatin analogues. Med Res Rev 19:388–407
Wender PA, Baryza JL, Bennett CE et al (2002) The practical synthesis of a novel and highly potent analogue of bryostatin. J Am Chem Soc 124:13648–13649
Wender PA, Mayweg AVW, VanDeusen CL (2003a) A concise, selective synthesis of the polyketide spacer domain of a potent bryostatin analogue. Org Lett 5:277–279
Wender PA, Koehler MFT, Sendzik M (2003b) A new synthetic approach to the C ring of known as well as novel bryostatin analogues. Org Lett 5:4549–4552
Wiegel J, Kevbrin VV (2004) Alkalithermophiles. Biochem Soc Trans 32:193–198
Wilkinson B, Moss SJ (2005) Biosynthetic engineering of natural products for lead optimization and development. Curr Opin Drug Dis Dev 8:748–750
Williams PG, Asolkar RN, Kondratyuk T et al (2007) Saliniketals A and B, bicyclic polyketides from the marine actinomycete Salinispora arenicola. J Nat Prod 70:83–88
Yang X, Zhang L, Guo B et al (2004) Preliminary study of a vincristine-producing endophytic fungus isolated from leaves of Catharanthus roseus. Zhong Cao Yao (Chinese Tradit. Herb. Drugs) 35:79–81
Yooseph S, Sutton G, Rusch DB et al (2007) The sorcerer II global ocean sampling expedition: expanding the universe of protein families. PLoS Biol 5(3):e16 doi:10.1371/journal.pbio.0050016. (Published 13 March 2007)
Yu T-W, Floss HG (2005) Ansamitocins (Maytansanoids). In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 321–338
Yu MJ, Kishi Y, Littlefield BA (2005) Discovery of E7389, a fully synthetic macrocyclic ketone analog of halichondrin B. In: Cragg GM, Kingston DGI, Newman DJ (eds) Anticancer agents from natural products. Taylor and Francis, Boca Raton, pp 241–266
Zhou G-X, Wijeratne EMK, Bigelow D et al (2004) Aspochalasins I, J, and K. J Nat Prod 67:328–332
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Cragg, G.M., Newman, D.J. Nature: a vital source of leads for anticancer drug development. Phytochem Rev 8, 313–331 (2009). https://doi.org/10.1007/s11101-009-9123-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11101-009-9123-y