Review Article | Published:

Drug development from marine natural products

Nature Reviews Drug Discovery volume 8, pages 6985 (2009) | Download Citation

Abstract

Drug discovery from marine natural products has enjoyed a renaissance in the past few years. Ziconotide (Prialt; Elan Pharmaceuticals), a peptide originally discovered in a tropical cone snail, was the first marine-derived compound to be approved in the United States in December 2004 for the treatment of pain. Then, in October 2007, trabectedin (Yondelis; PharmaMar) became the first marine anticancer drug to be approved in the European Union. Here, we review the history of drug discovery from marine natural products, and by describing selected examples, we examine the factors that contribute to new discoveries and the difficulties associated with translating marine-derived compounds into clinical trials. Providing an outlook into the future, we also examine the advances that may further expand the promise of drugs from the sea.

Key points

  • The large-scale collection, screening and discovery of novel marine natural products has propelled new chemical entities into the clinic for the treatment of pain, cancer and other disease states.

  • What is the status of discovery of 'drugs from the sea' and what hope do they offer for the alleviation of human suffering? The first two new drugs derived from marine organisms have now been approved — one for cancer and the other for chronic pain.

  • Other natural-product-inspired drugs, such as the anticancer compound eribulin mesylate, are in the pipeline.

  • We present the history and current stage of development for a selection of marine natural products, and examine the obstacles in their development into drugs.

  • We also discuss how new technologies in analytical sciences and 'genomic mining' are accelerating the pace of discovery.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    Transactions of the Drugs from the Sea Symposium, University of Rhode Island, 27–29 August 1967 1–297 (Marine Technology Society, Washington, DC, 1968).

  2. 2.

    & Marine natural products and related compounds in clinical and advanced preclinical trials. J. Nat. Prod. 67, 1216–1238 (2004).

  3. 3.

    & Natural products as sources of new drugs over the last 25 years. J. Nat. Prod. 70, 461–477 (2007).

  4. 4.

    & in Marine Anticancer Compounds in the Era of Targeted therapies 1st edn (ed. Chapner, B.) (Permanyer Publications, Barcelona, 2008).

  5. 5.

    & Contributions to the study of marine products. XXXII. The nucleosides of sponges. I. J. Org. Chem. 16, 981–987 (1951).

  6. 6.

    & Contributions to the study of marine products. XL. The nucleosides of sponges. IV. Spongosine. J. Org. Chem. 22, 226–228 (1956).

  7. 7.

    & Contributions to the study of marine products. XLIII. The nucleosides of sponges. V. The synthesis of spongosine. J. Org. Chem. 22, 1575–1557 (1957).

  8. 8.

    & The evolving role of natural products in drug discovery. Nature Rev. Drug Discovery 4, 206–220 (2004). This important, prescient review from scientists in a large pharmaceutical drug discovery programme presents the technical and logistical challenges for natural products discovery.

  9. 9.

    Liquid gold mine. Chem. Engin. News 85, 22–28 (2007).

  10. 10.

    in Drugs from the Sea (ed. Fusetani, N.) 120–133 (Karger, Basel, 2000).

  11. 11.

    et al. Peptide neurotoxins from fish-hunting cone snails. Science 230, 1338–1343 (1985).

  12. 12.

    & Conus venoms: a rich source of novel ion channel-targeted peptides. Physiol. Rev. 84, 41–68 (2004).

  13. 13.

    , , & Calcium-channel diversity and neurotransmitter release — the ω-conotoxins and ω-agatoxins. Ann. Rev. Biochem. 63, 823–867 (1994).

  14. 14.

    , , , & Determination of disulfide bridge pattern in ω-conopeptides. Int. J. Pept. Protein Res. 46, 320–325 (1995).

  15. 15.

    , & Roles of individual disulfide bonds in the stability and folding of an ω-conotoxin. Biochemistry 37, 9851–9861 (1998).

  16. 16.

    et al. Neuronal calcium-channel antagonists — discrimination between calcium-channel subtypes using ω-conotoxin from Conus magus venom. Biochemistry 26, 2086–2090 (1987).

  17. 17.

    , , , & Transmitter release from presynaptic terminals of electric organ: inhibition by the calcium channel antagonist ω Conus toxin. J. Neurosci. 7, 2390–2396 (1987).

  18. 18.

    , , , & Structural and dynamic characterization of ω -conotoxin MVIIA: the binding loop exhibits slow conformational exchange. Biochemistry 39, 3908–3919 (2000).

  19. 19.

    , , , & Tyr13 Is essential for the activity of ω -conotoxin MVIIA and GVIA, specific N-type calcium channel blockers. Biochem. Biophys. Res. Commun. 206, 449–454 (1995).

  20. 20.

    , , & Neuroanatomical distribution of receptors for a novel voltage-sensitive calcium-channel antagonist, SNX-230 (ω -conopeptide MVIIC). Brain Res. 653, 258–266 (1994).

  21. 21.

    et al. Selective N-type neuronal voltage-sensitive calcium channel blocker, SNX-111, produces spinal antinociception in rat models of acute, persistent and neuropathic pain. J. Pharmacol. Exp. Ther. 279, 1243–1249 (1996).

  22. 22.

    et al. Characterization of the binding of ω -conopeptides to different classes of non-L-type neuronal calcium channels. Mol. Cell. Neurosci. 5, 219–228 (1994).

  23. 23.

    et al. Composition and therapeutic utility of conotoxins from genus Conus. Patent status 1996–2000 Exp. Opin. Ther. Patents 11, 603–623 (2001).

  24. 24.

    & Pharmacotherapeutic potential of ω-conotoxin MVIIA (SNX-111), an N-type neuronal calcium channel blocker found in the venom of Conus magus. Toxicon 36, 1651–1658 (1998).

  25. 25.

    , , , & Effects of intrathecal administration of ziconotide, a selective neuronal N-type calcium channel blocker, on mechanical allodynia and heat hyperalgesia in a rat model of postoperative pain. Pain 84, 151–158 (2000).

  26. 26.

    Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr. Med. Chem. 11, 3029–3040 (2004).

  27. 27.

    Peptide leads new class of chronic pain drugs. Nature Biotech. 23, 399 (2005).

  28. 28.

    Conus toxins: targets and properties. IDrugs 7, 1011–1016 (2004).

  29. 29.

    et al. in Food–Drugs from the Sea: Proceedings (ed. Youngken, H. W. Jr) 281–294 (Marine Technology Society, Washington, DC, 1969).

  30. 30.

    et al. Ecteinascidin-729, Ecteinascidin-743, Ecteinascidin-745, Ecteinascidin-759a, Ecteinascidin-759b, and Ecteinascidin-770 — potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata. J. Org. Chem. 55, 4512–4515 (1990).

  31. 31.

    et al. Antitumor tetrahyrodisoquinoline alkaloids from the colonial ascidian Ecteinascidia turbinata. J. Org. Chem. 55, 4508–4512 (1990).

  32. 32.

    , , & Additional antitumor ecteinascidins from a Caribbean tunicate: crystal structures and activities in vivo. Proc. Nat. Acad. Sci. USA 89, 11456–11460 (1992).

  33. 33.

    , & Enantioselective total synthesis of ecteinascidin 743. J. Am. Chem. Soc. 118, 9202–9203 (1996).

  34. 34.

    & A new, more efficient, and effective process for the synthesis of a key pentacyclic intermediate for production of ecteinascidin and phthalascidin antitumor agents. Org. Lett. 2, 993–996 (2000).

  35. 35.

    et al. Synthesis of ecteinascidin ET-743 and Phthalascidin Pt-650 from cyanosafracin B. Org. Lett. 2, 2545–2548 (2000).

  36. 36.

    , & Ecteinascidin 743: a novel anticancer drug with a unique mechanism of action. Anticancer Drugs 13, 545–555 (2002).

  37. 37.

    et al. DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 35, 13303–13309 (1996).

  38. 38.

    & Ecteinascidin 743: a minor groove alkylator that bends DNA toward the major groove. J. Med. Chem. 42, 2493–2497 (1999).

  39. 39.

    et al. The inefficiency of incisions of ecteinascidin 743-DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent. Chem. Biol. 8, 1033–1049 (2001).

  40. 40.

    et al. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nature Med. 7, 961–966 (2001). An excellent technical paper describing the excision repair inhibition mechanism that is unique to ET-743.

  41. 41.

    et al. Final results of a phase II trial of 3-HR infusion trabectedin in patients with recurrent sarcomas. Ann. Oncol. 17, 167–167 (2006).

  42. 42.

    et al. Phase II study of trabectedin in pretreated patients with advanced colorectal cancer. Clin. Colorectal Cancer 6, 522–528 (2007).

  43. 43.

    et al. A phase II study of Yondelis® (trabectedin, ET-743) as a 24-h continuous intravenous infusion in pretreated advanced breast cancer Br. J. Cancer 94, 1610–1614 (2006).

  44. 44.

    et al. Trabectedin for women with ovarian carcinoma after treatment with platinum and taxanes fails. J. Clin. Oncol. 23, 1867–1874 (2005).

  45. 45.

    et al. Phase II study of ecteinascidin-743 in advanced pretreated soft tissue sarcoma patients. J. Clin. Oncol. 22, 890–899 (2004).

  46. 46.

    et al. Therapeutic impact of ET-743 (Yondelis; trabectidin), a new marine-derived compound, in sarcoma. Curr. Op. Orthopaed. 14, 419–428 (2003).

  47. 47.

    et al. Progress in the clinical development of new marine-derived anticancer compounds. Anticancer Drugs 15, 321–329 (2004).

  48. 48.

    et al. A phase II and pharmacokinetic study of ecteinascidin 743 in patients with gastrointestinal stromal tumors. Oncologist 7, 531–538 (2002).

  49. 49.

    et al. A phase II study of ET-743/trabectedin ('Yondelis') for patients with advanced gastrointestinal stromal tumours. Eur. J. Cancer 40, 1327–1331 (2004).

  50. 50.

    et al. Effective combination of ET-743 and doxorubicin in sarcoma: preclinical studies. Cancer Chemother. Pharmacol. 52, 131–138 (2003).

  51. 51.

    , , , & Sequence-dependent enhancement of cytotoxicity produced by ecteinascidin 743 (ET-743) with doxorubicin or paclitaxel in soft tissue sarcoma cells. Clin. Canc. Res. 7, 3251–3257 (2001).

  52. 52.

    et al. Combination of trabectedin and irinotecan is highly effective in a human rhabdomyosarcoma xenograft. Anticancer Drugs 16, 811–815 (2005).

  53. 53.

    et al. In-vitro cytotoxicity of ET-743 (Trabectedin, Yondelis), a marine anti-cancer drug, in the Hep G2 cell line: influence of cytochrome P450 and phase II inhibition, and cytochrome P450 induction. Anticancer Drugs 16, 935–943 (2005).

  54. 54.

    et al. Comparison of four modulators of drug metabolism as protectants against the hepatotoxicity of the novel antitumor drug yondelis (ET-743) in the female rat and in hepatocytes in vitro. Cancer Chemother. Pharmacol. 53, 305–312 (2004).

  55. 55.

    et al. Complete protection by high-dose dexamethasone against the hepatotoxicity of the novel antitumor drug yondelis (ET-743) in the rat. Cancer Res. 63, 5902–5908 (2003).

  56. 56.

    , & Hepatotoxicity and metabolism of trabectedin: a literature review. Pharmacol. Res. 51, 391–398 (2005).

  57. 57.

    et al. Didemnin B. The first marine compound entering clinical trials as an antineoplastic agent. Invest. New Drugs 4, 279–284 (1986).

  58. 58.

    & Natural products as probes of cell biology: 20 years of didemnin research. Med. Res. Rev. 22, 102–145 (2002).

  59. 59.

    Antitumor Compounds from Tunicates. Med. Res. Rev. 1, 1–27 (2003).

  60. 60.

    , , , & Structures of the didemnins, antiviral and cytotoxic depsipeptides from a Carribean tunicate. J. Am. Chem. Soc. 103, 1857–1859 (1981).

  61. 61.

    et al. Didemnins: antiviral and antitumor depsipeptides from a caribbean tunicate. Science 212, 933–935 (1981).

  62. 62.

    et al. Total synthesis of didemnins A, B, and C. J. Am. Chem. Soc. 109, 6856–6848 (1987).

  63. 63.

    , , & The complete spectral assignment of didemnin B and nordidemnin B. Tetrahedron Lett. 30, 3053–3056 (1989).

  64. 64.

    Structures of the Didemnins. Thesis, Univ. Illinois (1983).

  65. 65.

    et al. Crystal and molecular structure of didemnin B, an antiviral and cytotoxic depsipeptide. Proc. Natl Acad. Sci. USA 85, 4118–4122 (1988).

  66. 66.

    , & The antiproliferative agent didemnin B uncompetitively inhibits palmitoyl protein thioesterase. Biochemistry 37, 10488–10492 (1998).

  67. 67.

    , & Didemnin binds to the protein palmitoyl thioesterase responsible for infantile neuronal ceroid lipofuscinosis. Proc. Natl Acad. Sci. USA 93, 4316–4319 (1996).

  68. 68.

    et al. Mechanism of action of didemnin B, a depsipeptide from the sea. Cancer Lett. 23, 279–288 (1984).

  69. 69.

    & Mechanism of protein synthesis inhibition by didemnin B in vitro. Biochemistry 34, 9177–9184 (1995).

  70. 70.

    et al. Inhibition of protein synthesis by didemnin B: how EF-1a mediates inhibition of translocation. Biochemistry 39, 4339–4346 (2000).

  71. 71.

    , , & Structural basis for the binding of didemnins to human elongation factor eEF1A and rationale for the potent antitumor activity of these marine natural products. J. Med. Chem. 47, 4439–4452 (2004).

  72. 72.

    , , , & GTP-dependent binding of the antiproliferative agent didemnin to elongation factor 1 α. J. Biol. Chem. 269, 15411–15414 (1994). Illustrates the 'chemical biological' approach to the identification of protein targets of natural product drugs, and the importance of discriminating high- and low-affinity binding partners (see also reference 67)

  73. 73.

    , , & Inhibition of protein synthesis by didemnin B is not sufficient to induce apoptosis in human mammary carcinoma (MCF7) cells. Biochem. Pharmacol. 58, 1067–1074 (1999).

  74. 74.

    et al. Cell cycle phase perturbations and apoptosis in tumour cells induced by aplidine. Br. J. Cancer 86, 1510–1517 (2002).

  75. 75.

    , & Protein tyrosine kinase inhibitors prevent didemnin B-induced apoptosis in HL-60 cells. FEBS Lett. 383, 1–5 (1996).

  76. 76.

    & Rapamycin inhibits didemnin B-induced apoptosis in human HL-60 cells: evidence for the possible involvement of FK506-binding protein 25. Immunol. Cell Biol. 77, 242–248 (1999).

  77. 77.

    & Didemnins A and B. Effectiveness against cutaneous herpes simplex virus in mice. Antiviral Res. 3, 269–274 (1983).

  78. 78.

    , , & Antiproliferative effect of dehydrodidemnin B (DDB), a depsipeptide isolated from Mediterranean tunicates. Cancer Lett. 102, 31–37 (1996).

  79. 79.

    , , & Phase I clinical and pharmacokinetic investigation of didemnin B, a cyclic depsipeptide. Eur. J. Cancer Clin. Oncol. 24, 1699–1706 (1988).

  80. 80.

    , , & Application of a new preclinical drug screening system for cancer of the large bowel. Cancer Chemother. Pharmacol. 21, 31–34 (1988).

  81. 81.

    , & Didemnin B induces cell death by apoptosis: the fastest induction of apoptosis ever described. Biochem. Biophys. Res. Commun. 215, 1130–1136 (1995).

  82. 82.

    , , & Cytotoxicity and neurocytotoxicity of new marine anticancer agents evaluated using in vitro assays. Cancer Chemother. Pharmacol. 44, 312–318 (1999).

  83. 83.

    , , & A phase I clinical trial of didemnin B. Cancer 68, 2550–2554 (1991).

  84. 84.

    , , & Phase I clinical study of didemnin B. Invest. New Drugs 16, 51–56 (1998).

  85. 85.

    et al. Phase I/II clinical trial of didemnin B in non-small-cell lung cancer: neuromuscular toxicity is dose-limiting. Cancer Chemother. Pharmacol. 29, 145–149 (1991).

  86. 86.

    et al. Phase II clinical and pharmacological study of didemnin B in patients with metastatic breast cancer. Invest. New Drugs 10, 113–117 (1992).

  87. 87.

    et al. Phase II clinical trial of didemnin B in previously treated small cell lung cancer. Invest. New Drugs 12, 243–249 (1994).

  88. 88.

    et al. Didemnin B in favorable histology non-Hodgkin's lymphoma: a phase II study of the National Cancer Institute of Canada Clinical Trials Group. Invest. New Drugs 13, 257–260 (1995).

  89. 89.

    et al. Phase II trail of didemnin B in previously treated non-Hodgkin's lymphoma: an Eastern Cooperative Oncology Group (ECOG) Study. Am. J. Clin. Oncol. 23, 273–277 (2000).

  90. 90.

    , , & A phase II study of Didemnin B (NSC 325319) in advanced malignant melanoma: an Eastern Cooperative Oncology Group study (PB687). Invest. New Drugs 16, 259–263 (1999).

  91. 91.

    et al. Phase II clinical trial of didemnin B in patients with recurrent or refractory anaplastic astrocytoma or glioblastoma multiforme (NSC 325319). Invest. New Drugs 17, 179–182 (1999).

  92. 92.

    et al. Phase II study of didemnin B in central nervous system tumors: a Southwest Oncology Group study. Invest. New Drugs 16, 331–332 (1999).

  93. 93.

    et al. Pharmaceutical development of anticancer agents from marine sources. Anticancer Drugs 11, 793–811 (2000).

  94. 94.

    & WO9104985 (A1) (1991).

  95. 95.

    et al. Aplidin induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C. Oncogene 21, 7533–7544 (2002).

  96. 96.

    , & Rapid and selective apoptosis in human leukemic cells induced by Aplidine through a Fas/CD95- and mitochondrial-mediated mechanism. Clin. Cancer Res. 9, 1535–1545 (2003).

  97. 97.

    , , , & Mitochondrial cytochrome c release is caspase-dependent and does not involve mitochondrial permeability transition in didemnin B-induced apoptosis. Oncogene 20, 4085–4094 (2001).

  98. 98.

    et al. Aplidin induces apoptosis in human cancer cells via glutathione depletion and sustained activation of the epidermal growth factor receptor, Src, JNK, and p38 MAPK. J. Biol. Chem. 278, 241–250 (2003).

  99. 99.

    , , , & JNK activation is critical for Aplidin-induced apoptosis. Oncogene 23, 4673–4680 (2004).

  100. 100.

    et al. Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF–VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4. Leukemia 17, 52–59 (2003).

  101. 101.

    et al. VEGF inhibition and cytotoxic effect of aplidin in leukemia cell lines and cells from acute myeloid leukemia. Ann. Oncol. 16, 1667–1674 (2005).

  102. 102.

    , , & Establishment and characterisation of a human carcinoma cell line with acquired resistance to Aplidin. Br. J. Cancer 91, 1405–1413 (2004).

  103. 103.

    et al. Effect of aplidine in acute lymphoblastic leukaemia cells. Br. J. Cancer 89, 763–773 (2003).

  104. 104.

    et al. In vitro toxicity of ET-743 and aplidine, two marine-derived antineoplastics, on human bone marrow haematopoietic progenitors. comparison with the clinical results. Eur. J. Cancer 38, 1395–1404 (2002).

  105. 105.

    , & Didemnin B induces apoptosis in proliferating but not resting peripheral blood mononuclear cells. Apoptosis 7, 407–412 (2002).

  106. 106.

    et al. In vitro cytotoxicity of aplidin and crossresistance with other cytotoxic drugs in childhood leukemic and normal bone marrow and blood samples: a rational basis for clinical development. Leukemia 17, 1338–1343 (2003).

  107. 107.

    , , , & In vitro toxicity of three new antitumoral drugs (trabectedin, aplidin, and kahalalide F) on hematopoietic progenitors and stem cells. Exp. Hematol. 31, 1104–1111 (2003).

  108. 108.

    et al. Antiangiogenic activity of aplidine, a new agent of marine origin. Br. J. Cancer 90, 2418–2424 (2004).

  109. 109.

    , , & Inhibition by Aplidine of the aggregation of the prion peptide PrP 106–126 into β-sheet fibrils. Biochem. Biophys. Acta 1639, 133–139 (2003).

  110. 110.

    , , , & Hemiasterlin and geodiamolide TA: two new cytotoxic peptides from the marine sponge Hemiasterella minor (Kirkpatrick). Tetrahedron Lett. 35, 4453–4456 (1994).

  111. 111.

    , , , & Cytotoxic peptides from the marine sponge Cymbastela sp. Tetrahedron 51, 10653–10662 (1995).

  112. 112.

    , , & Hemiasterlin methyl ester. Acta Cryst. Sec. C C52, 1525–1527 (1996).

  113. 113.

    et al. Cytotoxic and tubulin-interactive hemiasterlins from Auletta sp. and Siphonochalina spp. sponges. Bioorg. Med. Chem. 7, 1611–1615 (1999).

  114. 114.

    , , & Cytotoxic peptides hemiasterlin, hemiasterlin A and hemiasterlin B induce mitotic arrest and abnormal spindle formation. Cancer Chemother. Pharmacol. 39, 223–226 (1997).

  115. 115.

    , , & Interactions of the sponge-derived antimitotic tripeptide hemiasterlin with tubulin: comparison with dolastatin 10 and cryptophycin 1. Biochemistry 38, 14302–14310 (1999).

  116. 116.

    et al. Synthesis and antimitotic/cytotoxic activity of hemiasterlin analogues. J. Nat. Prod. 66, 183–199 (2003).

  117. 117.

    et al. Synthesis and biological activity of analogues of the antimicrotubule agent N,β,β-trimethyl-L-phenylalanyl-N1-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]-N1,3-dimethyl-L-valinamide(HTI-286). J. Med. Chem. 47, 4774–4786 (2004).

  118. 118.

    et al. D-piece modifications of the hemiasterlin analog HTI-286 produce potent tubulin inhibitors. Bioorg. Med. Chem. Lett. 14, 4353–4358 (2004).

  119. 119.

    et al. Synthesis and activity of novel analogs of hemiasterlin as inhibitors of tubulin polymerization: modification of the A segment. Bioorg. Med. Chem. Lett. 14, 5317–5322 (2004).

  120. 120.

    et al. Tubulin inhibitors. Synthesis and biological activity of HTI-286 analogs with B-segment heterosubstituents. Bioorg. Med. Chem. Lett. 14, 4329–4332 (2004).

  121. 121.

    et al. Probing the interaction of HTI-286 with tubulin using a stilbene analogue. J. Am. Chem. Soc. 126, 9898–9899 (2004).

  122. 122.

    et al. Biophysical characterization of the interactions of HTI-286 with tubulin heterodimer and microtubules. Biochemistry 42, 13484–13495 (2003).

  123. 123.

    & Localization of the antimitotic peptide and depsipeptide binding site on β-tubulin. Biochemistry 43, 13955–13962 (2004).

  124. 124.

    et al. Two photoaffinity analogues of the tripeptide, hemiasterlin, exclusively label α-tubulin. Biochemistry 44, 6844–6857 (2005).

  125. 125.

    et al. Tumor cells resistant to a microtubule-depolymerizing hemiasterlin analogue, HTI-286, have mutations in α- or β-tubulin and increased microtubule stability. Biochemistry 43, 13944–13954 (2004).

  126. 126.

    et al. Cells resistant to HTI-286 do not overexpress P-glycoprotein but have reduced drug accumulation and a point mutation in α-tubulin. Mol. Cancer Ther. 3, 1319–1327 (2004).

  127. 127.

    et al. HTI-286, a synthetic analogue of the tripeptide hemiasterlin, is a potent antimicrotubule agent that circumvents P-glycoprotein-mediated resistance in vitro and in vivo. Cancer Res. 63, 1838–1845 (2003).

  128. 128.

    et al. Phase 1 and pharmacological study of HTI-286, a novel antimicrotubule agent: correlation of neutropenia with time above a threshold serum concentration. Proc. Am. Soc. Clin. Oncol. 22, 516 (2003).

  129. 129.

    et al. Targeting prostate cancer with HTI-286, a synthetic analog of the marine sponge product hemiasterlin Int. J. Cancer: 122, 2368–2376 (2008).

  130. 130.

    The chemistry and biology of discodermolide. ChemBiochem 1, 171–175 (2000).

  131. 131.

    (+)-discodermolide: a marine natural product against cancer. Scientific World Journal 4, 415–436 (2004).

  132. 132.

    , , , & Discodermolide — a new, marine-derived immunosuppressive compound. I. In vitro studies. Transplantation 52, 650–656 (1991).

  133. 133.

    , , , & Discodermolide — a new, marine-derived immunosuppressive compound. II. In vivo studies. Transplantation 52, 656–661 (1991).

  134. 134.

    , , , & Immunosuppression by discodermolide. Ann. NY Acad. Sci. 696, 94–107 (1993).

  135. 135.

    , , & Discodermolide: a new bioactive polyhydroxylated lactone from the marine sponge Discodermia dissoluta. J. Org. Chem. 55, 4912–4915 (1990).

  136. 136.

    , , & Discodermolide: a new bioactive polyhydroxylated lactone from the marine sponge Discodermia dissoluta [Erratum to document cited in CA113(9):75187b]. J. Org. Chem. 56, 1346 (1991).

  137. 137.

    , , & Total synthesis of the immunosuppressive agent (−)-discodermolide. J. Am. Chem. Soc. 115, 12621–12622 (1993).

  138. 138.

    , & Distinct binding and cellular properties of synthetic (+)- and (−)-discodermolides. Chem. Biol. 1, 67–71 (1994). A good example of enantioselective bioactivity of natural and unnatural antipodes of marine-derived drugs.

  139. 139.

    , , , & Total synthesis of the potent microtubule-stabilizing agent (+)-discodermolide. J. Org. Chem. 68, 6646–6660 (2003).

  140. 140.

    & Total synthesis of (+)-discodermolide: an improved endgame exploiting a Still-Gennari-type olefination with a C1-C8 β-ketophosphonate fragment. Org. Lett. 6, 4933–4936 (2004).

  141. 141.

    et al. A second-generation total synthesis of (+)-discodermolide: the development of a practical route using solely substrate-based stereocontrol. J. Org. Chem. 70, 150–160 (2005).

  142. 142.

    , , , & Gram-scale synthesis of (+)-discodermolide. Org. Lett. 1, 1823–1826 (1999).

  143. 143.

    et al. Evolution of a gram-scale synthesis of (+)-discodermolide. J. Am. Chem. Soc. 122, 8654–8664 (2000).

  144. 144.

    , , & A practical improvement, enhancing the large-scale synthesis of (+)-discodermolide: a third-generation approach. Org. Lett. 5, 4405–4408 (2003).

  145. 145.

    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).

  146. 146.

    et al. Large-scale synthesis of the anti-cancer marine natural product (+)-discodermolide. Part 2: synthesis of fragments C1–6 and C9–14 Org. Proc. Res. Dev. 8, 101–106 (2004).

  147. 147.

    et al. Large-scale synthesis of the anti-cancer marine natural product (+)-discodermolide. Part 3: synthesis of fragment C15–21 Org. Proc. Res. Dev. 8, 107–112 (2004). References 145–147 describe the challenge for production, met by a tour de force multi-step, total synthesis, of a complex, rare marine-derived drug. The synthesis of 65 g of discodermolide shows what is possible when the target is highly desirable.

  148. 148.

    et al. Large-scale synthesis of the anti-cancer marine natural product (+)-discodermolide. Part 4: preparation of fragment C7–24 Org. Proc. Res. Dev. 8, 113–121 (2004).

  149. 149.

    et al. Large-scale synthesis of the anti-cancer marine natural product (+)-discodermolide. Part 5: linkage of fragments C1–6 and C7–24 and finale. Org. Proc. Res. Dev. 8, 122–130 (2004).

  150. 150.

    , & (+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks taxol binding and results in mitotic arrest. Chem. Biol. 3, 287–293 (1996).

  151. 151.

    et al. Discodermolide, a cytotoxic marine agent that stabilizes microtubules more potently than taxol. Biochemistry 35, 243–250 (1996).

  152. 152.

    et al. The microtubule-stabilizing agent discodermolide competitively inhibits the binding of paclitaxel (Taxol) to tubulin polymers, enhances tubulin nucleation reactions more potently than paclitaxel, and inhibits the growth of paclitaxel-resistant cells. Mol. Pharmacol. 52, 613–622 (1997).

  153. 153.

    et al. Taxol and discodermolide represent a synergistic drug combination in human carcinoma cell lines. Clin. Cancer Res. 6, 1978–1987 (2000).

  154. 154.

    & Discodermolide: just another microtubule-stabilizing agent? No! A lesson in synergy. Clin. Cancer Res. 6, 1613–1615 (2000).

  155. 155.

    et al. Synergistic suppression of microtubule dynamics by discodermolide and paclitaxel in non-small cell lung carcinoma cells. Cancer Res. 64, 4957–4964 (2004).

  156. 156.

    & Differential mitotic responses to microtubule-stabilizing and -destabilizing drugs. Cancer Res. 62, 1935–1938 (2002).

  157. 157.

    et al. Late activation of apoptotic pathways plays a negligible role in mediating the cytotoxic effects of discodermolide and epothilone B in non-small cell lung cancer cells. Cancer Res. 62, 4081–4088 (2002).

  158. 158.

    et al. Suppression of microtubule dynamics by discodermolide by a novel mechanism is associated with mitotic arrest and inhibition of tumor cell proliferation. Mol. Cancer Ther. 2, 1303–1311 (2003).

  159. 159.

    , , & Discodermolide interferes with the binding of tau protein to microtubules. FEBS Lett. 539, 34–36 (2003).

  160. 160.

    , & Both microtubule-stabilizing and microtubule-destabilizing drugs inhibit hypoxia-inducible factor-1α accumulation and activity by disrupting microtubule function. Cancer Res. 65, 9021–9028 (2005).

  161. 161.

    , , & The microtubule stabilizing agent discodermolide is a potent inducer of accelerated cell senescence. Cell Cycle 4, 501–507 (2005).

  162. 162.

    et al. Discodermolide analogues as the chemical component of combination bacteriolytic therapy. Bioorg. Med. Chem. Lett. 15, 3623–3626 (2005).

  163. 163.

    et al. A phase I pharmacokinetic (PK) trial of XAA296A (Discodermolide) administered every 3 wks to adult patients with advanced solid malignancies. J. Clin. Oncol. 22, 2025 (2004).

  164. 164.

    et al. Pharmaceuticals from cultured algae. J. Ind. Microbiol. 5, 113–124 (1990).

  165. 165.

    et al. Total structures of cryptophycins, potent antitumor depsipeptides from the blue-green-alga Nostoc sp strain Gsv-224. J. Am. Chem. Soc. 116, 4729–4737 (1994).

  166. 166.

    et al. Arenastatin A, a potent cytotoxic depsipeptide from the Okinawan marine sponge Dysidea arenaria. Tetrahedron Lett. 35, 7969–7972 (1994).

  167. 167.

    et al. Total synthesis of cryptophycins — revision of the structures of cryptophycin-A and cryptophycin-C. J. Am. Chem. Soc. 117, 2479–2490 (1995).

  168. 168.

    , , , & Cryptophycin-induced hyperphosphorylation of Bcl-2, cell cycle arrest and growth inhibition in human H460 NSCLC cells. Cancer Chemother. Pharmacol. 47, 170–178 (2001).

  169. 169.

    , & Cryptophycin 1 binds to tubulin at a site distinct from the colchicine binding site and at a site that may overlap the vinca binding site. Cancer Lett. 107, 53–57 (1996).

  170. 170.

    , , , & Interaction of cryptophycin 1 with tubulin and microtubules. FEBS Lett. 377, 59–61 (1995).

  171. 171.

    & Mechanism of action of cryptophycin — interaction with the vinca alkaloid domain of tubulin. J. Biol. Chem. 271, 6192–6198 (1996).

  172. 172.

    , , , & Mechanism of action of the unusually potent microtubule inhibitor cryptophycin 1. Biochemistry 36, 12948–12953 (1997).

  173. 173.

    et al. In vitro pharmacology of cryptophycin 52 (LY355703) in human tumor cell lines. Cancer Chemother. Pharmacol. 43, 115–125 (1999).

  174. 174.

    et al. Phase I and pharmacological studies of the cryptophycin analogue LY355703 administered on a single intermittent or weekly schedule. Eur. J. Cancer 38, 2388–2396 (2002).

  175. 175.

    et al. Phase I trial of the cryptophycin analogue LY355703 administered as an intravenous infusion on a day 1 and 8 schedule every 21 days. Clin. Cancer Res. 8, 2524–2529 (2002).

  176. 176.

    et al. Phase 2 study of cryptophycin 52 (LY355703) in patients previously treated with platinum based chemotherapy for advanced non-small cell lung cancer. Lung Cancer 39, 197–199 (2003).

  177. 177.

    et al. Cryptophycins-309, 249 and other cryptophycin analogs: Preclinical efficacy studies with mouse and human tumors. Investig. New Drugs 23, 213–224 (2005).

  178. 178.

    The dolastatins. Fortschr. Chem. Org. Naturst. 70, 1–79 (1997).

  179. 179.

    et al. The isolation and structure of a remarkable marine animal antineoplastic constituent — Dolastatin 10. J. Am. Chem. Soc. 109, 6883–6885 (1987).

  180. 180.

    Progress in the discovery of biosynthetic anticancer drugs. J. Nat. Prod. 59, 812–821 (1996).

  181. 181.

    et al. The absolute-configuration and synthesis of natural (−)-Dolastatin-10. J. Am. Chem. Soc. 111, 5463–5465 (1989).

  182. 182.

    , & 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 (1990).

  183. 183.

    , & Binding of dolastatin-10 to tubulin at a distinct site for peptide antimitotic agents near the exchangeable nucleotide and vinca alkaloid sites. J. Biol. Chem. 265, 17141–17149 (1990).

  184. 184.

    , , & Dolastatin-15, a potent antimitotic depsipeptide derived from Dolabella auricularia: interaction with tubulin and effects on cellular microtubules. Biochem. Pharmacol. 43, 2637–2645 (1992).

  185. 185.

    , , & Sustained intracellular retention of dolastatin 10 causes its potent antimitotic activity. Mol. Pharmacol. 57, 180–187 (2000).

  186. 186.

    et al. Phase I trial of dolastatin-10 (NSC 376128) in patients with advanced solid tumors. Clin. Cancer Res. 5, 525–531 (1999).

  187. 187.

    et al. Novel marine-derived anticancer agents: a phase I clinical, pharmacological, and pharmacodynamic study of dolastatin 10 (NSC 376128) in patients with advanced solid tumors. Clin. Cancer Res. 6, 1293–1301 (2000).

  188. 188.

    et al. Phase II study of dolastatin-10 in patients with hormone-refractory metastatic prostate adenocarcinoma. Clin. Cancer Res. 6, 4205–4208 (2000).

  189. 189.

    et al. Phase II study of dolastatin-10 in patients with advanced non-small-cell lung cancer. Ann. Oncol. 11, 227–228 (2000).

  190. 190.

    et al. Dolastatin-10 in metastatic melanoma: a phase II and pharmokinetic trial of the California Cancer Consortium. Invest. New Drugs 19, 335–340 (2001).

  191. 191.

    et al. Phase II study of dolastatin-10 as first-line treatment for advanced colorectal cancer. Am. J. Clin. Oncol. 25, 451–453 (2002).

  192. 192.

    et al. Phase II trial of dolastatin-10, a novel anti-tubulin agent, in metastatic soft tissue sarcomas. Sarcoma 8, 107–111 (2004).

  193. 193.

    et al. Phase II trial of dolastatin-10 in patients with advanced breast cancer. Invest. New Drugs 23, 257–261 (2005).

  194. 194.

    et al. Phase II trials of dolastatin-10 in advanced pancreaticobiliary cancers. Invest. New Drugs 23, 489–493 (2005).

  195. 195.

    & Marine natural products and related compounds in clinical and advanced preclinical trials. J. Nat. Prod. 67, 1216–1238 (2004).

  196. 196.

    et al. Antitumor activity of TZT-1027, a novel dolastatin 10 derivative. Jpn. J. Cancer Res. 88, 316–327 (1997).

  197. 197.

    et al. Phase I and pharmacokinetic study of TZT-1027, a novel synthetic dolastatin 10 derivative, administered as a 1-hour intravenous infusion every 3 weeks in patients with advanced refractory cancer. Ann. Oncol. 15, 671–679 (2004).

  198. 198.

    et al. Phase I and pharmacokinetic study of the dolastatin 10 analogue TZT-1027, given on days 1 and 8 of a 3-week cycle in patients with advanced solid tumors. Clin. Cancer Res. 11, 3806–3813 (2005).

  199. 199.

    et al. TZT-1027 elucidates antitumor activity through direct cytotoxicity and selective blockade of blood supply. Anticancer Res. 24, 2201–2208 (2004).

  200. 200.

    et al. Characterization of the interaction of TZT-1027, a potent antitumor agent, with tubulin. Jpn. J. Cancer Res. 91, 737–747 (2000).

  201. 201.

    & , Halichondrins — antitumor polyether macrolides from a marine sponge. Pure App. Chem. 58, 701–710 (1986).

  202. 202.

    et al. Norhalichondrin A: an antitumor polyether macrolide from a marine sponge. J. Am. Chem. Soc. 107, 4796–4798 (1985).

  203. 203.

    et al. Isolation and structure of halistatin 1 from the eastern Indian Ocean marine sponge Phakellia carteri. J. Org. Chem. 58, 2538–2543 (1993).

  204. 204.

    et al. Antineoplastic agents. 219. Isolation and structure of the cell growth inhibitory constituents from the western Pacific marine sponge Axinella sp. J. Med. Chem. 34, 3339–3340 (1991).

  205. 205.

    et al. Halichondrin B and homohalichondrin B, marine natural products binding in the vinca domain of tubulin. Discovery of tubulin-based mechanism of action by analysis of differential cytotoxicity data. J. Biol. Chem., 266, 15882–15889 (1991).

  206. 206.

    et al. Comparison of the activities of the truncated halichondrin B analog NSC 707389 (E7389) with those of the parent compound and a proposed binding site on tubulin. Mol. Pharmacol. 70, 1866–1875 (2006).

  207. 207.

    D et al. Total synthesis of halichondrin B and norhalichondrin B. J. Am. Chem. Soc. 114, 3162–3164 (1992).

  208. 208.

    , , , & in Drugs from the Sea (ed. Fusetani, N.) 134–153 (Karger, Basel, 2000).

  209. 209.

    , , , & Halichondrins: cytotoxic polyether macrolides. EP0572109 (B1) (1993).

  210. 210.

    et al. The discovery and development of marine compounds with pharmaceutical potential. J. Biotechnol. 70, 15–25 (1999).

  211. 211.

    , & New synthetic route to the C14-C38 segment of halichondrins. J. Org. Chem. 62, 7552–7553 (1997).

  212. 212.

    , , , , & Structure–activity relationships of halichondrin B analogues: modifications at C30-C38. Bioorg. Med. Chem. Lett., 10, 1029–1032 (2000).

  213. 213.

    et al. Macrocyclic analogs and methods of their use and preparation. WO9965894 (A1) (1999).

  214. 214.

    , & in Anticancer Agents from Natural Products (eds Cragg, G. M., Kingston, D. G. I. & Newman, D. J.) 241–265 (Taylor and Francis, Boca Raton, 2005).

  215. 215.

    et al. In vitro and in vivo anticancer activities of synthetic macrocyclic ketone analogues of halichondrin B. Cancer Res. 61, 1013–1021 (2001).

  216. 216.

    et al. E7389, a novel anti-tubulin, in patients with refractory breast cancer. J. Clin. Oncol. 24 (Suppl. 18), 653 (2006).

  217. 217.

    et al. Phase II study of eribulin mesylate (E7389) halichondrin B analog in patients with refractory breast cancer. J. Clin. Oncol. 25 (Suppl. 18), 1034 (2007).

  218. 218.

    , et al. Phase II study of eribulin mesylate (E7389), a mechanistically novel inhibitor of microtubule dynamics, in patients with advanced non-small cell lung cancer (NSCLC). J. Clin. Oncol. 25 (Suppl. 18), 7546 (2007).

  219. 219.

    PR Newswire. Eribulin Mesylate Demonstrated Anti-Tumor Activity in Heavily Pretreated Patients With Advanced Breast Cancer. PR Newswire web site [online], <> (2008).

  220. 220.

    & Kahalalide F: a bioactive depsipeptide from the Sacoglossan mollusk Elysia rufescens and the green alga Bryopsis sp. J. Am. Chem. Soc. 115, 5825–5826 (1993).

  221. 221.

    , & The absolute stereochemistry of kahalalide F. Tetrahedron 55, 7739–7746 (1999).

  222. 222.

    , , & Kahalalides: bioactive peptide from a marine mollusk Elysia rufescens and its algal diet Bryopsis sp. J. Org. Chem. 61, 6594–6600 (1996).

  223. 223.

    et al. Structure of cypemycin, a new peptide antibiotic. Tetrahedron Lett. 35, 8001–8004 (1994).

  224. 224.

    et al. Hassallidin A, a glycosylated lipopeptide with antifungal activity from the cyanobacterium Hassallia sp. J. Nat. Prod. 68, 695–700 (2005).

  225. 225.

    , , & Chemical defenses of the sacoglossan mollusk Elysia rufescens and its host alga Bryopsis sp. J. Chem. Ecol. 27, 2287–2299 (2001).

  226. 226.

    , , , & Synthesis and structure determination of kahalalide F. J. Am. Chem. Soc. 123, 11398–11401 (2001).

  227. 227.

    , & Stereochemistry of kahalalide F. J. Nat. Prod. 66, 1466–1470 (2003).

  228. 228.

    , & The antitumoral compound Kahalalide F acts on cell lysosomes. Cancer Lett. 99, 43–50 (1996).

  229. 229.

    et al. Kahalalide F, a new marine-derived compound, induces oncosis in human prostate and breast cancer cells. Mol. Cancer Ther. 2, 863–872 (2003).

  230. 230.

    , , , & Kahalalide F induces necrosis-like cell death that involves depletion of ErbB3 and inhibition of Akt signaling. Mol. Pharmacol. 68, 502–510 (2005).

  231. 231.

    et al. The mechanism of action of Kahalalide F: variable cell permeability in human hepatoma cell lines. Eur. J. Cancer 41, 1637–1644 (2005).

  232. 232.

    et al. Chemical and enzymatic stability of a cyclic depsipeptide, the novel, marine-derived, anti-cancer agent kahalalide F. Anticancer Drugs 12, 575–582 (2001).

  233. 233.

    , , & Preclinical toxicity studies of kahalalide F, a new anticancer agent: single and multiple dosing regimens in the rat. Cancer Chemother. Pharmacol. 50, 333–340 (2002).

  234. 234.

    et al. Phase I clinical and pharmacokinetic study of Kahalalide F in patients with advanced androgen refractory prostate cancer. Clin. Cancer Res. 11, 1854–1862 (2005).

  235. 235.

    et al. A phase I clinical and pharmacokinetic (PK) study with Kahalalide F (KF) in patients (pts) with advanced solid tumors (AST) with a continuous weekly (W) 1-hour iv infusion schedule. Eur. J. Cancer 38 (Suppl.), S33 (2002).

  236. 236.

    et al. Isolation and structure of bryostatin-1. J. Am. Chem. Soc. 104, 6846–6848 (1982).

  237. 237.

    et al. The large-scale isolation of bryostatin-1 from Bugula neritina following current good manufacturing practices. J. Nat. Prod. 54, 1265–1270 (1991).

  238. 238.

    Supply issues complicate trek of chemicals from sea to market. Chem. Eng. News 73, 42–44 (1995).

  239. 239.

    et al. Total synthesis of bryostatin 2. J. Am. Chem. Soc. 121, 7540–7552 (1999).

  240. 240.

    et al. Total synthesis of bryostatin 3. Angew. Chem. Int. Ed. Engl. 39, 2290–2294 (2000).

  241. 241.

    Evolution of synthetic strategies for highly functionalized natural products: a successful route to bryostatin 3. Bull. Chem. Soc. Jap. 77, 875–885 (2004).

  242. 242.

    et al. Synthesis of bryostatin-7. J. Am. Chem. Soc. 112, 7407–7408 (1990).

  243. 243.

    et al. Synthesis of bryostatins.1. construction of the C(1)-C(16) fragment. J. Org. Chem. 54, 2817–2825 (1989).

  244. 244.

    , , & Synthesis of the bryostatin 1 northern hemisphere (C1-C16) via desymmetrization by ketalization/ring-closing metathesis. Org. Lett. 6, 4045–4048 (2004).

  245. 245.

    & Towards the asymmetric synthesis of bryostatin 1. Pure Appl. Chem. 68, 715–718 (1996).

  246. 246.

    , , , & Inhibition of phorbol ester-induced T-cell proliferation by bryostatin is associated with rapid degradation of protein-kinase-C. J. Immunol. 150, 1195–1204 (1993).

  247. 247.

    et al. Synthesis of the first members of a new class of biologically active bryostatin analogues. J. Am. Chem. Soc. 120, 4534–4535 (1998).

  248. 248.

    et al. Modeling of the bryostatins to the phorbol ester pharmacophore on protein kinase C. Proc. Natl Acad. Sci. USA 85, 7197–7201 (1988).

  249. 249.

    et al. Bryostatin 1, an activator of protein kinase C, inhibits tumor promotion by phorbol esters in SENCAR mouse skin. Carcinogenesis 8, 1343–1346 (1987).

  250. 250.

    et al. In vivo administration of the anticancer agent bryostatin 1 activates platelets and neutrophils and modulates protein kinase C activity. Cancer Res. 53, 2810–2815 (1993).

  251. 251.

    , , , & Modulation of gene-expression in the acute promyelocytic leukemia-cell line Nb4. Leukemia 7, 1817–1823 (1993).

  252. 252.

    , & Effect of bryostatin-1 on the in vitro radioprotective capacity of recombinant granulocyte macrophage colony-stimulating factor (Rgm-Csf) toward committed human myeloid progenitor cells (Cfu-Gm). Exp. Hematol. 20, 34–42 (1992).

  253. 253.

    & Chemistry and clinical biology of the bryostatins. Bioorg. Med. Chem. 8, 1841–1860 (2000).

  254. 254.

    et al. A phase II study of bryostatin 1 in metastatic malignant melanoma. Br. J. Cancer 78, 1337–1341 (1998).

  255. 255.

    et al. Phase I trial of bryostatin 1 in relapsed lymphoma and CLL. Blood 88, 2269 (1996).

  256. 256.

    et al. Phase II study of bryostatin 1 in patients with relapsed multiple myeloma. Invest. New Drugs 19, 245–247 (2001).

  257. 257.

    et al. Phase II trial of bryostatin 1 in patients with relapsed low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia Clin. Cancer Res. 6, 825–828 (2000).

  258. 258.

    et al. Phase Ib trial of bryostatin 1 in patients with refractory malignancies. Clin. Cancer Res. 4, 611–618 (1998).

  259. 259.

    & The clinical development of the bryostatins. Anticancer Drugs 13, 673–683 (2002).

  260. 260.

    et al. Bryostatin 1, a novel antineoplastic agent and protein-kinase-C activator, induces human myalgia and muscle metabolic defects — a P-31 magnetic-resonance spectroscopic study. Br. J. Cancer 72, 998–1003 (1995).

  261. 261.

    et al. A phase II trial of bryostatin-1 in patients with metastatic or recurrent squamous cell carcinoma of the head and neck. Invest. New Drugs 20, 123–127 (2002).

  262. 262.

    et al. A phase II trial of bryostatin 1 in the treatment of metastatic colorectal cancer. Clin. Cancer Res. 7, 38–42 (2001).

  263. 263.

    et al. Phase II evaluation of bryostatin-1 in metastatic melanoma. Melanoma Res. 11, 183–188 (2001).

  264. 264.

    et al. A phase II trial of bryostatin-1 for patients with metastatic renal cell carcinoma. Cancer 89, 615–618 (2000).

  265. 265.

    et al. A phase II trial of bryostatin-I administered by weekly 24-hour infusion in recurrent epithelial ovarian carcinoma. Br. J. Cancer 89, 1152–1154 (2003).

  266. 266.

    et al. Phase I trial and correlative laboratory studies of bryostatin I (NSC 339555) and high-dose 1-β-D-arabinofuranosylcytosine in patients with refractory acute leukemia. Clin. Cancer Res. 8, 2123–2133 (2002).

  267. 267.

    et al. Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B-cell malignancies. Clin. Cancer Res. 9, 5929–5935 (2003).

  268. 268.

    Multi-center Phase II study of sequential paclitaxel and bryostatin-1 (NSC 339555) in patients with untreated, advanced gastric or gastroesophageal junction adenocarcinoma. Invest. New Drugs 24, 353–357 (2006).

  269. 269.

    & Targeting the cell cycle: a new approach to cancer therapy. J. Clin. Oncol. 23, 9408–9421 (2005).

  270. 270.

    & Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J. Chem. Inf. Comput. Sci. 43, 218–227 (2003).

  271. 271.

    et al. Genome sequencing reveals complex secondary metabolome in the marine actinomycete Salinispora tropica. Proc. Natl Acad. Sci. USA 104, 10376–10381 (2007).

  272. 272.

    & New drugs from marine microbes: the tide is turning. J. Ind. Microbiol. Biotechnol. 33, 539–544 (2006).

  273. 273.

    Bacterial symbionts: prospects for the sustainable production of invertebrate-derived pharmaceuticals. Curr. Med. Chem. 13, 39–50 (2006).

  274. 274.

    et al. bryA: An unusual modular polyketide synthase gene from the uncultivated bacterial symbiont of the marine bryozoan Bugula neritina. Chem. Biol. 11, 1543–1552 (2004).

  275. 275.

    et al. Identification of the putative bryostatin polyketide synthase gene cluster from “Candidatus Endobugula sertula”, the uncultivated microbial symbiont from the marine bryozoan Bugula neritina. J. Nat. Prod. 70, 67–74 (2007).

  276. 276.

    , The Iliad, (7th century, B.C). Fagles, R. (translation). Penguin Books (1990).

  277. 277.

    , The Odyssey (7th century B. C.). Fagles, R. (translation). Penguin Books (2006).

  278. 278.

    et al. Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus Salinospora. Angew. Chem. Intl. Ed. 42, 355–357 (2003).

  279. 279.

    , , , & Salinispora gen nov., sp. nov., Salinispora arenicola sp. nov., and S. tropica sp. nov., obligate marine actinomycetes belonging to the family Micromonosporaceae. Internat. J. System. Appl. Microbiol. 55, 1759–1766 (2005).

  280. 280.

    et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 8, 407–419 (2005).

  281. 281.

    et al. Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 111, 1654–1664 (2008).

  282. 282.

    et al. Discovery and development of the anticancer agent salinosporamide A (NPI-0052). Bioorg. Med. Chem. 5 Nov 2008 (doi:10.1016/j.bmc.2008.10.075). This article, and several within the same issue of the journal, chronicle the discovery of key marine antitumour drugs by the original investigators and illustrates issues of procurement, scale-up, production and clinical investigations.

  283. 283.

    & Phorboxazoles A and B — potent cytostatic macrolides from marine sponge Phorbas sp. J. Am. Chem. Soc. 117, 8126–8131 (1995).

  284. 284.

    , , & Absolute configuration of phorboxazoles A and B from the marine sponge Phorbas sp.1. macrolide and hemiketal rings. J. Am. Chem. Soc. 118, 9422–9423 (1996).

  285. 285.

    Absolute configuration of phorboxazoles A and B from the marine sponge, Phorbas sp.2. C43 and complete stereochemistry. Tetrahedron Lett. 37, 7879–7880 (1996).

  286. 286.

    , , , & Chlorocyclopropane macrolides from the marine sponge Phorbas sp. Assignment of the absolute configurations of phorbasides A and B by quantitative CD. J. Am. Chem. Soc. 129, 4150–4151 (2007).

  287. 287.

    , , & Phorbasides A-E, cytotoxic chlorocyclopropane macrolide glycosides from the marine sponge Phorbas sp. CD determination of C-methyl sugar configurations. J. Org. Chem. 73, 3699–3706 (2008).

Download references

Acknowledgements

The authors are grateful to J. Blunt (University of Canterbury, New Zealand) and D. Newman (Developmental Therapeutics Program, US National Cancer Institute) for valuable discussions, and to S. Lopez-Legintil (University of North Carolina, Wilmington, USA) for kind permission to reproduce the underwater image of Ecteinascidia turbinata (figure 2b). Some of the authors' research described herein was supported by grants to T.F.M. from the US National Cancer Institute, National Institutes of Health (CA122256 and CA085602).

Author information

Affiliations

  1. Department of Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, 9500 Gilman Drive, MC 0358, La Jolla, California 92093, USA.

    • Tadeusz F. Molinski
    • , Doralyn S. Dalisay
    • , Sarah L. Lievens
    •  & Jonel P. Saludes
  2. Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, USA.

    • Sarah L. Lievens
    •  & Jonel P. Saludes

Authors

  1. Search for Tadeusz F. Molinski in:

  2. Search for Doralyn S. Dalisay in:

  3. Search for Sarah L. Lievens in:

  4. Search for Jonel P. Saludes in:

Corresponding author

Correspondence to Tadeusz F. Molinski.

About this article

Publication history

Published

DOI

https://doi.org/10.1038/nrd2487

Further reading