Natural Products Diversity of Marine Ascidians (Tunicates; Ascidiacea) and Successful Drugs in Clinical Development

doi:10.1007/s13659-016-0115-5

摘要/Abstract

摘要： This present study reviewed the chemical diversity of marine ascidians and their pharmacological applications, challenges and recent developments in marine drug discovery reported during 1994-2014, highlighting the structural activity of compounds produced by these specimens. Till date only 5% of living ascidian species were studied from <3000 species, this study represented from family didemnidae (32%), polyclinidae (22%), styelidae and polycitoridae (11-12%) exhibiting the highest number of promising MNPs. Close to 580 compound structures are here discussed in terms of their occurrence, structural type and reported biological activity. Anti-cancer drugs are the main area of interest in the screening of MNPs from ascidians (64%), followed by anti-malarial (6%) and remaining others. FDA approved ascidian compounds mechanism of action along with other compounds status of clinical trials (phase 1 to phase 3) are discussed here in. This review highlights recent developments in the area of natural products chemistry and biotechnological approaches are emphasized.

关键词: Cancer, Cytotoxicity, Diversity, Metabolites, Pharmacology

Abstract: This present study reviewed the chemical diversity of marine ascidians and their pharmacological applications, challenges and recent developments in marine drug discovery reported during 1994-2014, highlighting the structural activity of compounds produced by these specimens. Till date only 5% of living ascidian species were studied from <3000 species, this study represented from family didemnidae (32%), polyclinidae (22%), styelidae and polycitoridae (11-12%) exhibiting the highest number of promising MNPs. Close to 580 compound structures are here discussed in terms of their occurrence, structural type and reported biological activity. Anti-cancer drugs are the main area of interest in the screening of MNPs from ascidians (64%), followed by anti-malarial (6%) and remaining others. FDA approved ascidian compounds mechanism of action along with other compounds status of clinical trials (phase 1 to phase 3) are discussed here in. This review highlights recent developments in the area of natural products chemistry and biotechnological approaches are emphasized.

Key words: Cancer, Cytotoxicity, Diversity, Metabolites, Pharmacology

Satheesh Kumar Palanisamy, N. M. Rajendran, Angela Marino. Natural Products Diversity of Marine Ascidians (Tunicates; Ascidiacea) and Successful Drugs in Clinical Development[J]. 应用天然产物, 2017, 7(1): 1-111.

参考文献

1. P. Proksch, R. Edrada, R. Ebel, Appl. Micro. Biotechnol. 59(2-3), 125-134 (2002) 2. N. Shenkar, B.J. Swalla, PLoS ONE 6(6), e20657 (2011) 3. B.S. Davidson, Chem. Rev. 93(5), 1771-1791 (1993) 4. J.W. Blunt, B.R. Copp, R.A. Keyzers, M.H. Munro, M.R. Prinsep, Nat. Prod. Rep. 31(2), 160-258 (2014) 5. J.W. Blunt, B.R. Copp, R.A. Keyzers, M.H. Munro, M.R. Prinsep, Nat. Prod. Rep. 32(2), 116-211 (2015) 6. C. Findlay, V.J. Smith, Fish. Shell. Immunol. 5(8), 645-658 (1995) 7. D.J. Faulkner, Nat. Prod. Rep. 18(1), 1R-49R (2001) 8. W. Wang, O. Takahashi, T. Oda, T. Nakazawa, K. Ukai, R.E.P. Mangindaan, H. Rotinsulu, D.S. Wewengkang, H. Kobayashi, S. Tsukamoto, M. Namikoshi, Tetrahedron 65, 9598-9603 (2009) 9. M. Menna, Phytochem. Rev. 8(2), 461-472 (2009) 10. E. Zubia, M.J. Ortega, Tetrahedron 54, 14597-14602 (1998) 11. M.S. Donia, B.J. Hathaway, S. Sudek, M.G. Haygood, M.J. Rosovitz, J. Ravel, E.W. Schmidt, Nat. Chem.Biol. 2(12), 729-735 (2006) 12. W. Fenical, Phytochemistry 15(4), 511-512 (1976) 13. J.W. Blunt, B.R. Copp, R.A. Keyzers, M.H. Munro, M.R. Prinsep, Nat. Prod. Rep. 30(2), 237-323 (2013) 14. J. Fayette, I.R. Coquard, L. Alberti, H. Boyle, P. Méeus, A.V. Decouvelaere et al., Curr. Opin. Oncol. 18(4), 347-353 (2006) 15. C. Le Tourneau, E. Raymond, S. Faivre, Ther. Clin. Risk Manag. 3(2), 341 (2007) 16. S. López-Legentil, X. Turon, Zool. Scr. 34(1), 3-14 (2005) 17. A. García, M.J. Vazquez, E. Quinoa, R. Riguera, C. Debitus, J. Nat. Prod. 59, 782-785 (1996) 18. A.R. Carroll, V.M. Avery, J. Nat. Prod. 72, 696-699 (2009) 19. H. Yamazaki, D.S. Wewengkang, T. Nishikawa, H. Rotinsulu, R.E.P. Mangindaan, M. Namikoshi, Mar. Drugs 10, 349-357 (2012) 20. M.S. Agrawal, B.F. Bowden, Nat. Prod. Res. 21, 782-786 (2007) 21. G.P. Gunawardana, F.E. Koehn, A.Y. Lee, J. Clardy, H.Y. He, D.J. Faulkner, J. Org. Chem. 57(5), 1523-1526 (1992) 22. G. Koren-goldshlager, M. Aknin, Y. Kashman, J. Nat. Prod. 63(6), 830-831 (2000) 23. G.P. Gunawardana, S. Kohmoto, S.P. Gunasekera, O.J. McConnell, F.E. Koehn, J. Am. Chem. Soc. 110(14), 4856-4858 (1988) 24. A.R. Carroll, P.J. Scheuer, J. Org, Chemistry 55(14), 4426-4431 (1990) 25. P.J. Nilar, B.K. Sidebottom, B.K. Carté, M.S. Butler, J. Nat. Prod. 65, 1198-1200 (2002) 26. P. Wipf, Y. Uto, J. Org. Chem. 65, 1037-1049 (2000) 27. L.J. Perez, D.J. Faulkner, J. Nat. Prod. 66(2), 247-250 (2003) 28. S.L. You, J.W. Kelly, Tetrahedron Lett. 46, 2567-2570 (2005) 29. Y. Yonezawa, N. Tani, C.G. Shin, Bull. Chem. Soc. Jpn. 78(8), 1492-1499 (2005) 30. A. Rudi, L. Chill, M. Aknin, Y. Kashman, J. Nat. Prod. 66, 575-577 (2003) 31. S.L. You, J.W. Kelly, Tetrahedron 61, 241-249 (2005) 32. R. Finlayson, A. Brackovic, A. Simon-Levert, B. Banaigs, R.F. O'Toole, C.H. Miller, B.R. Copp, Tetrahedron Lett. 52, 837-840 (2011) 33. A. Plubrukarn, B.S. Davidson, J. Org. Chem. 63, 1657-1659 (1998) 34. E. Delfourne, C. Roubin, J. Bastide, J. Org. Chem. 65, 5476-5479 (2000) 35. E. Piers, R. Britton, R.J. Andersen, J. Org. Chem. 65, 530-535 (2000) 36. S.M. Verbitski, C.L. Mayne, R.A. Davis, G.P. Concepcion, C.M. Ireland, J. Org. Chem. 67(20), 7124-7126 (2002) 37. G.D. Artman, S.M. Weinreb, Org. Lett. 5, 1523-1526 (2003) 38. A. Numata, C. Takahashi, Y. Ito, T. Takada, K. Kawai, Y. Usami et al., Tetrahedron Lett. 34(14), 2355-2358 (1993) 39. A.S. Ratnayake, W.Y. Yoshida, S.L. Mooberry, T.K. Hemscheidt, J. Org. Chem. 66(26), 8717-8721 (2001) 40. A.S. Ratnayake, W.Y. Yoshida, S.L. Mooberry, T.K. Hemscheidt, J. Org. Chem. 68(4), 1640-1640 (2003) 41. J.A. May, R.K. Zeidan, B.M. Stoltz, Tetrahedron Lett. 44(6), 1203-1205 (2003) 42. T.H. Trieu, J. Dong, Q. Zhang, B. Zheng, T.Z. Meng, X. Lu, X.X. Shi, Eur. J. Org. Chem. 16, 3271-3277 (2013) 43. W. Wang, S.J. Nam, B.C. Lee, H. Kang, J. Nat. Prod. 71(2), 163-166 (2008) 44. S. Tsukamoto, H. Kato, H. Hirota, N. Fusetani, J. Nat. Prod. 57(11), 1606-1609 (1994) 45. R. Galinier, E. Roger, P.E. Sautiere, A. Aumelas, B. Banaigs, G. Mitta, J. Pept. Sci. 15, 48-55 (2009) 46. M.D. Vera, M.M. Joullie, Med. Res. Rev. 22(2), 102-145 (2002) 47. R.W. Schumacher, B.S. Davidson, Tetrahedron 51(37), 10125-10130 (1995) 48. D.R. Appleton, A.N. Pearce, G. Lambert, R.C. Babcock, B.R. Copp, Tetrahedron 58, 9779-9783 (2002) 49. I.H. Lee, Y. Cho, R.I. Lehrer, Comp. Biochem. Physiol. 118, 515-521 (1997) 50. P. Schupp, T. Poehner, R. Edrada, R. Ebel, A. Berg, V. Wray, P. Proksch, J. Nat. Prod. 66, 272-275 (2003) 51. H. Liu, S.B. Pratasik, T. Nishikawa, T. Shida, K. Tachibana, T. Fujiwara, H. Nagai, H. Kobayashi, M. Namikoshi, Tetrahedron Lett. 45, 7015-7017 (2004) 52. H. Liu, T. Fujiwara, T. Nishikawa, Y. Mishima, H. Nagai, T. Shida, K. Tachibana, H. Kobayashi, R.E.P. Mangindaan, M. Namikoshi, Tetrahedron 61, 8611-8615 (2005) 53. T. Nakazawa, J. Xu, T. Nishikawa, T. Oda, A. Fujita, K. Ukai, R.E.P. Mangindaan, H. Rotinsulu, H. Kobayashi, M. Namikoshi, J. Nat. Prod. 70, 439-442 (2007) 54. A. Simon-Levert, A. Arrault, N. Bontemps-Subielos, C. Canal, B. Banaigs, J. Nat. Prod. 68(9), 1412-1415 (2005) 55. A. Simon-Levert, A. Aze, N. Bontemps-Subielos, B. Banaigs, A.M. Genevière, Chem. Biol. Interact. 168, 106-116 (2007) 56. H. Kobayashi, Y. Miyata, K. Okada, T. Fujita, T. Iwashita, Y. Nakao, N. Fusetani, S. Matsunaga, Tetrahedron 63, 6748-6754 (2007) 57. N. Bontemps, D. Bry, S. López-Legentil, A. Simon-Levert, C. Long, B. Banaigs, J. Nat. Prod. 73, 1044-1048 (2010) 58. M. Tadesse, M.B. Strøm, J. Svenson, M. Jaspars, B.F. Milne, V. Tørfoss, J.H. Andersen, E. Hansen, K. Stensvåg, T. Haug, Org. Lett. 12, 4752-4755 (2010) 59. M. Tadesse, J. Svenson, M. Jaspars, M.B. Strøm, M.H. Abdelrahman, J.H. Andersen, E. Hansen, P.E. Kristiansen, K. Stensvg, T. Haug, Tetrahedron Lett. 52, 1804-1806 (2011) 60. L. Núnez-Pons, R. Forestieri, R.M. Nieto, M. Varela, M. Nappo, J. Rodríguez, C. Jiménez, F. Castelluccio, M. Carbone, A. Ramos-Espla, M. Gavagnin, C. Avila, Polar Biol. 33, 1319-1329 (2010) 61. L.H. Franco, E.B.D.K. Joffé, L. Puricelli, M. Tatian, A.M. Seldes, J.A. Palermo, J. Nat. Prod. 61, 1130-1132 (1998) 62. A.M. Seldes, M.F.R. Brasco, L.H. Franco, J.A. Palermo, Nat. Prod. Res. 21, 555-563 (2007) 63. L. Núnez-Pons, M. Carbone, J. Vazquez, J. Rodríguez, R.M. Nieto, M.M. Varela, M. Gavagnin, C. Avila, Mar. Drugs 10, 1741-1764 (2012) 64. D.R. Appleton, C.S. Chuen, M.V. Berridge, V.L. Webb, B.R. Copp, J. Org. Chem. 74, 9195-9198 (2009) 65. R. Riguera, J. Mar. Biotechnol. 5, 187-193 (1997) 66. D. Bry, B. Banaigs, C. Long, N. Bontemps, Tetrahedron Lett. 52, 3041-3044 (2011) 67. T.H. Won, J.E. Jeon, S.H. Kim, S.H. Lee, B.J. Rho, D.C. Oh, K.B. Oh, J. Shin, J. Nat. Prod. 75, 2055-2061 (2012) 68. T.H. Won, J.E. Jeon, S.H. Lee, B.J. Rho, K.B. Oh, J. Shin, Bioorg. Med. Chem. 20, 4082-4087 (2012) 69. J. Sikorska, S. Parker-Nance, M.T. Davies-Coleman, O.B. Vining, A.E. Sikora, K.L. McPhail, J. Nat. Prod. 75, 1824-1827 (2012) 70. W. Wang, H. Kim, S.J. Nam, B.J. Rho, H. Kang, J. Nat. Prod. 75, 2049-2054 (2012) 71. G.A. Mohamed, S.R.M. Ibrahim, J.M. Badr, D.T.A. Youssef, Tetrahedron 70, 35-40 (2014) 72. I.H. Lee, C. Zhao, T. Nguyen, L. Menzel, A.J. Waring, M.A. Sherman, R.I. Lehrer, J. Pept. Res. 58, 445 (2001) 73. J.A. Tincu, A.G. Craig, S.W. Taylor, Biochem. Biophys. Res. Commun. 270, 421-424 (2000) 74. J.A. Tincu, L.P. Menzel, R. Azimov, J. Sands, T. Hong, A.J. Waring, R.I. Lehrer, J. Biol. Chem. 278(15), 13546-13553 (2003) 75. L.A. McDonald, T.L. Capson, G. Krishnamurthy, W.D. Ding, G.A. Ellestad, V.S. Bernan, W.M. Maiese, P. Lassota, C.Discafani, R.A. Kramer, C.M. Ireland, J. Am. Chem. Soc. 118, 10898-10899 (1996) 76. D.R. Appleton, A.N. Pearce, B.R. Copp, Tetrahedron 66, 4977-4986 (2010) 77. M.H. Kossuga, J.B. Macmillan, E.W. Rogers, T.F. Molinski, G.G.F. Nascimento, R.M. Rocha, R.G.S. Berlinck, Notes 2004, 1879-1881 (1879) 78. T.F. Molinski, Curr. Med. Chem. 3, 197-220 (2004) 79. C.J. Smith, R.L. Hettich, J. Jompa, A. Tahir, C.M. Ireland, J. Org. Chem. 63, 4147-4150 (1998) 80. C.H. Ahn, T.H. Won, H. Kim, J. Shin, K.B. Oh, Bioorg. Med. Chem. Lett. 23, 4099-4101 (2013) 81. P.A. Searle, T.F. Molinski, J. Org. Chem. 58(26), 7578-7580 (1993) 82. W.S. Jang, H.K. Kim, K.Y. Lee, S.A. Kim, Y.S. Han, I.H. Lee, FEBS Lett. 580, 1490-1496 (2006) 83. D. Smitha, M.M.K. Kumar, H. Ramana, D.V. Rao, Nat. Prod. Res. 28, 12-17 (2014) 84. J.L. Li, E. La Kim, H. Wang, J. Hong, S. Shin, C.K. Lee, J.H. Jung, Bioorg. Med. Chem. Lett. 23, 4701-4704 (2013) 85. R. Riccio, R.B. Kinnel, G. Bifulco, P.J. Scheuer, Tetrahedron Lett. 37(12), 1979-1982 (1996) 86. R.A. Davis, A.R. Carroll, G.K. Pierens, R.J. Quinn, J. Nat. Prod. 62, 419-424 (1999) 87. M.V.R. Reddy, M.R. Rao, D. Rhodes, M. Hansen, K. Rubins, F. Bushman, Y. Venkateswarlu, D.J. Faulkner, J. Med. Chem. 42, 1901-1907 (1999) 88. N. Gonzalez, J. Rodríguez, C. Jiménez, J. Org. Chem. 64(15), 5705-5707 (1999) 89. M.S. Donia, B. Wang, D.C. Dunbar, P.V. Desai, A. Patny, M. Avery, M.T. Hamann, J. Nat. Prod. 71, 941-945 (2008) 90. Z. Lu, M.K. Harper, C.D. Pond, L.R. Barrows, C.M. Ireland, R.M. Van Wagoner, J. Nat. Prod. 75, 1436-1440 (2012) 91. J. Mendiola, H. Hernandez, I. Sariego, L. Rojas, A. Otero, A. Ramírez, M. de los Angeles Chavez, A. Payrol, A. Hernandez, Trans. R Soc. Trop. Med. Hyg. 100, 909-916 (2006) 92. M.D. Lebar, K.N. Hahn, T. Mutka, P. Maignan, J.B. McClintock, C.D. Amsler, A. Van Olphen, D.E. Kyle, B.J. Baker, Bioorg. Med. Chem. 19, 5756-5762 (2011) 93. S.R. Walker, M.L. Czyz, J.C. Morris, Org. Lett. 16, 708-711 (2014) 94. S.B. Bharate, R.R. Yadav, S.I. Khan, B.L. Tekwani, M.R. Jacob, I.A. Khan, R.A. Vishwakarma, Medchem. Commun. 2013, 4 (1042) 95. M.S. Liberio, D. Sooraj, E.D. Williams, Y. Feng, R.A. Davis, Tetrahedron Lett. 52, 6729-6731 (2011) 96. S.T.S. Chan, A.N. Pearce, A.H. Januario, M.J. Page, M. Kaiser, R.J. McLaughlin, J.L. Harper, V.L. Webb, D. Barker, B.R. Copp, J. Org. Chem. 76, 9151-9156 (2011) 97. R. Finlayson, A.N. Pearce, M.J. Page, M. Kaiser, M.L. Bourguet-Kondracki, J.L. Harper, V.L. Webb, B.R. Copp, J. Nat. Prod. 74, 888-892 (2011) 98. S.T.S. Chan, A.N. Pearce, M.J. Page, M. Kaiser, B.R. Copp, J. Nat. Prod. 74, 1972-1979 (2011) 99. R.M. Van Wagoner, J. Jompa, A. Tahir, C.M. Ireland, J. Nat. Prod. 62(5), 794-797 (1999) 100. A.R. Carroll, B.D. Nash, S. Duffy, V.M. Avery, J. Nat. Prod. 75, 1206-1209 (2012) 101. C.F.C. Lam, A.N. Pearce, S.H. Tan, M. Kaiser, B.R. Copp, Mar. Drugs 11, 3472-3499 (2013) 102. A.R. Carroll, S. Duffy, V.M. Avery, J. Org. Chem. 75, 8291-8294 (2010) 103. D.E. Williams, R.E. Moore, V.J. Paul, J. Nat. Prod. 52(4), 732-739 (1989) 104. L.A. McDonald, C.M. Ireland, J. Nat. Prod. 55(3), 376-379 (1992) 105. M. Ishida, Y.T. Lee, T. Higashino, H. Seo, T. Nakamura, Jpn. J. Appl. Phys. 34(2S), 831 (1995) 106. E.W. Schmidt, J.T. Nelson, D.A. Rasko, S. Sudek, J.A. Eisen, M.G. Haygood, J. Ravel, Proc. Natl. Acad. Sci. USA 102, 7315-7320 (2005) 107. P.F. Long, W.C. Dunlap, C.N. Battershill, M. Jaspars, ChemBioChem 6, 1760-1765 (2005) 108. L.A. Morris, M. Jaspars, J.J. Kettenes-Van Den Bosch, K. Versluis, A.J.R. Heck, S.M. Kelly, N.C. Price, Tetrahedron 57, 3185-3197 (2001) 109. Y. Feng, R.A. Davis, M.L. Sykes, V.M. Avery, A.R. Carroll, D. Camp, R.J. Quinn, Tetrahedron Lett. 51(18), 2477-2479 (2010) 110. P.P. Simarro, G. Cecchi, J.R. Franco, M. Paone, A. Diarra, J.A. Ruiz Postigo, E.M. Fevre, R.C. Mattioli, J.G. Janini, PLoS Negl. Trop. Dis. 6(10), e1859 (2012) 111. W.Y. Yoshida, K.K. Lee, A.R. Carroll, P.J. Scheuer, Helv. Chem. Acta 75(5), 1721-1725 (1992) 112. R. Duran, E. Zubía, M.J. Ortega, S. Naranjo, J. Salva, Tetrahedron 55(46), 13225-13232 (1999) 113. S. Manzanaro, J. Salva, J.A. de la Fuente, J. Nat. Prod. 69, 1485-1487 (2006) 114. K. Ravinder, A. Vijender Reddy, P. Krishnaiah, P. Ramesh, S. Ramakrishna, H. Laatsch, Y. Venkateswarlu, Tetrahedron Lett. 46, 5475-5478 (2005) 115. S. Horii, Y. Kameda, J. Antibiot. 21, 665-667 (1986) 116. P. Krishnaiah, V.L.N. Reddy, G. Venkataramana, K. Ravinder, M. Srinivasulu, T.V. Raju, K. Ravikumar, D. Chandrasekar, S. Ramakrishna, Y. Venkateswarlu, J. Nat. Prod. 67, 1168-1171 (2004) 117. A.N. Pearce, E.W. Chia, M.V. Berridge, G.R. Clark, J.L. Harper, L. Larsen, E.W. Maas, M.J. Page, N.B. Perry, V.L. Webb, B.R. Copp, J. Nat. Prod. 70, 936-940 (2007) 118. A.N. Pearce, E.W. Chia, M.V. Berridge, E.W. Maas, M.J. Page, V.L. Webb, J.L. Harper, B.R. Copp, J. Nat. Prod. 70, 111-113 (2007) 119. C.L.R. Belmiro, M.T.L. Castelo-Branco, L.M.C. Melim, A. Schanaider, C. Elia, K. Madi, M.S.G. Pavao, H.S.P. de Souza, J. Biol. Chem. 284, 11267-11278 (2009) 120. J.L. Li, S.C. Han, E.S. Yoo, S. Shin, J. Hong, Z. Cui et al., J. Nat. Prod. 74(8), 1792-1797 (2011) 121. J.L. Li, B. Xiao, M. Park, E.S. Yoo, S. Shin, J. Hong, H.Y. Chung, H.S. Kim, J.H. Jung, J. Nat. Prod. 75, 2082-2087 (2012) 122. J.L. Li, E.L. Kim, H. Wang, J. Hong, S. Shin, C.K. Lee, J.H. Jung, Bioorg. Med. Chem. Lett. 23(16), 4701-4704 (2013) 123. R.P. Rajesh, A. Murugan, Pharmacology 4(1), 65-69 (2013) 124. M.P. Sauviat, J. Vercauteren, N. Grimaud, M. Jugé, M. Nabil, J.Y. Petit, J.F. Biard, J. Nat. Prod. 69, 558-562 (2006) 125. T. Ozawa, S. Aoyagi, C. Kibayashi, Org. Lett. 2, 2955-2958 (2000) 126. H. Tsuneki, Y. You, N. Toyooka, T. Sasaoka, H. Nemoto, J.A. Dani, I. Kimura, Biol. Pharm. Bull. 28, 611-614 (2005) 127. D.M. Tapiolas, B.F. Bowden, E. Abou-Mansour, R.H. Willis, J.R. Doyle, A.N. Muirhead, C. Liptrot, L.E. Llewellyn, C.W.W. Wolff, A.D. Wright, C.A. Motti, J. Nat. Prod. 72, 1115-1120 (2009) 128. J.C. Swersey, C.M. Ireland, L.M. Cornell, R.W. Peterson, J. Nat. Prod. 57(6), 842-845 (1994) 129. L.A. McDonald, J. Christopher Swersey, C.M. Ireland, A.R. Carroll, J.C. Coll, B.F. Bowden, C.R. Fairchild, L. Cornell, Tetrahedron 51, 5237-5244 (1995) 130. S. Yin, C. Cullinane, A.R. Carroll, R.J. Quinn, R.A. Davis, Tetrahedron Lett. 51, 3403-3405 (2010) 131. C.J. Henrich, R.W. Robey, K. Takada, H.R. Bokesch, S.E. Bates, S. Shukla, S.V. Ambudkar, J.B. Mcmahon, K.R. Gustafson, ACS Chem. Biol. 4, 637-647 (2009) 132. A. Rajasekaran, A. Muruga, P.R. Anand, R. Vijayakumar, T. Kumaresan, M.S. Ramasamy, Res. Pub. 3, 101-104 (2003) 133. A.R. Carroll, Y. Feng, B.F. Bowden, J.C. Coll, J. Org. Chem. 61, 4059-4061 (1996) 134. B.S. Lindsay, L.R. Barrows, B.R. Copp, Bioorg. Med. Chem. Lett. 5, 739-742 (1995) 135. A. Koulman, L.M.C. Pruijn, T.S. Sandstra, H.J. Woerdenbag, N. Pras, J. Biotechnol. 70(1-3), 85-88 (1999) 136. R.A. Davis, I.T. Sandoval, G.P. Concepcion, R. Moreira Da Rocha, C.M. Ireland, Tetrahedron 59, 2855-2859 (2003) 137. R.G. Berlinck, R. Britton, E. Piers, L. Lim, M. Roberge, R.M. da Rocha, R.J. Andersen, J. Org. Chem. 26, 9850-9856 (1998) 138. R. Britton, J.H.H.L. De Oliveira, R.J. Andersen, R.G.S. Berlinck, J. Nat. Prod. 64, 254-255 (2001) 139. L. Garrido, E. Zubía, M.J. Ortega, J. Salva, J. Nat. Prod. 65, 1328-1331 (2002) 140. A. Aiello, E. Fattorusso, P. Luciano, M. Menna, G. Esposito, T. Iuvone et al., Eur. J. Org. Chem. 5, 898-900 (2003) 141. A. Aiello, E. Fattorusso, P. Luciano, A. Macho, M. Menna, E. Munoz, J. Med. Chem. 48, 3410-3416 (2005) 142. A. Aiello, E. Fattorusso, P. Luciano, M. Menna, E. Calzado, F. Munoz, M. Bonadies, M.F. Sanasi, G. Cocco, R. Nicoletti, Bioorg. Med. Chem. 18, 719-727 (2010) 143. M. Menna, A. Aiello, F. D'Aniello, C. Imperatore, P. Luciano, R. Vitalone, C. Irace, R. Santamaria, Eur. J. Org. Chem. 16, 3241-3246 (2013) 144. A. Garcia, L.A. Lenis, C. Jiménez, C. Debitus, E. Quinoa, R. Riguera, Org. Lett. 2, 2765-2767 (2000) 145. H. Kang, W. Fenical, A.D. Ningalins, J. Org. Chem. 62(10), 3254-3262 (1997) 146. F. Plisson, M. Conte, Z. Khalil, X.C. Huang, A.M. Piggott, R.J. Capon, ChemMedChem 7, 983-990 (2012) 147. P.C. Jimenez, D.V. Wilke, E.G. Ferreira, R. Takeara, M.O. De Moraes, E.R. Silveira, T.M.D.C. Lotufo, N.P. Lopes, L.V. Costa-Lotufo, Mar. Drugs 10, 1092-1102 (2012) 148. R.B. Kinnell, P.J. Scheuerl, T. Mall, R. May, J. Org. Chem. 13, 6327-6329 (1992) 149. P.A. Horton, R.E. Longley, O.J. McConnell, L.M. Ballas, Experientia 50(9), 843-845 (1994) 150. P. Schupp, C. Eder, P. Proksch, V. Wray, B. Schneider, M. Herderich, V. Paul, J. Nat. Prod. 62(7), 959-962 (1999) 151. P. Schupp, K. Steube, C. Meyer, P. Proksch, Cancer Lett. 174(2), 165-172 (2001) 152. P. Schupp, P. Proksch, V. Wray, J. Nat. Prod. 65, 295-298 (2002) 153. W.D. Jarvis, A.J. Turner, L.E. Povrik, R.S. Taylor, S. Grant, Cancer Res. 54, 1707-1714 (1994) 154. T.M. Akiyama, M. Shimizu, T. Okabe, T.S. Akinaga, AntiCancer Drugs 10, 67-78 (1999) 155. I. Utz, S. Hoffer, U. Regenass, W. Hilbe, J. Thaler, H. Grunicke, J. Hofmann, Int. J. Cancer 57, 104-110 (1994) 156. P.C. Jimenez, S.C. Fortier, T.M.C. Lotufo, C. Pessoa, M.E.A. Moraes, M.O. De Moraes, L.V. Costa-Lotufo, J. Exp. Mar. Biol. Ecol. 287, 93-101 (2003) 157. P.C. Jimenez, D.V. Wilke, R. Takeara, T.M.C. Lotufo, C. Pessoa, M.O. de Moraes, N.P. Lopes, L.V. Costa-Lotufo, Comp. Biochem. Physiol. 151, 391-398 (2008) 158. A. Aiello, S. Carbonelli, G. Esposito, E. Fattorusso, T. Iuvone, M. Menna, J. Nat. Prod. 63, 1590-1592 (2000) 159. A. Crispino, A. De Giulio, S. De Rosa, S. De Stefano, A. Milone, N. Zavodnik, J. Nat. Prod. 57(11), 1575-1577 (1994) 160. M.R. Rao, D.J. Faulkner, J. Nat. Prod. 67(6), 1064-1066 (2004) 161. A.D. Patil, A.J. Freyer, L. Killmer, G. Zuber, B. Carte, A.J. Jurewicz, R.K. Johnson, Nat. Prod. Lett. 10, 225-229 (1997) 162. T. Oda, K. Kamoshita, S. Maruyama, K. Masuda, M. Nishimoto, J. Xu, K. Ukai, R.E.P. Mangindaan, M. Namikoshi, Biol. Pharm. Bull. 30, 385-387 (2007) 163. L. Garrido, E. Zubía, M.J. Ortega, J. Salva, J. Org. Chem. 68, 293-299 (2003) 164. S.N. Fedorov, O.S. Radchenko, L.K. Shubina, N.N. Balaneva, A.M. Bode, V.A. Stonik, Z. Dong, Pharm. Res. 23, 70-81 (2006) 165. M. Tadesse, J. Svenson, K. Sepc, L. Trembleau, M. Engqvist, J.H. Andersen, M. Jaspars, K. Stensva, J. Nat. Prod. 77(2), 364-369 (2014) 166. E.A. Santalova, V.A. Denisenko, D.V. Berdyshev, D.L. Aminin, Nat. Prod. Commun. 3(10), 1617-1620 (2008) 167. R.A. Davis, A.R. Carroll, R.J. Quinn, J. Nat. Prod. 61, 959-960 (1998) 168. M.A. Rashid, K.R. Gustafson, M.R. Boyd, J. Nat. Prod. 64, 1454-1456 (2001) 169. Y.R. Torres, T.S. Bugni, R.G.S. Berlinck, C.M. Ireland, A. Magalhaes, A.G. Ferreira, R.M. Da Rocha, J. Org. Chem. 67, 5429-5432 (2002) 170. M. Martínez-García, M. Díaz-Valdés, A. Ramos-Espla, N. Salvador, P. Lopez, E. Larriba, J. Antón, Mar. Drugs 5, 52-70 (2007) 171. N. Bontemps, F. Gattacceca, C. Long, O.P. Thomas, B. Banaigs, J. Nat. Prod. 76, 1801-1805 (2013) 172. S.M. Reddy, M. Srinivasulu, N. Satyanarayana, A.K. Kondapi, Y. Venkateswarlu, Tetrahedron 61, 9242-9247 (2005) 173. A.R. Quesada, M.G. Gravalos, J.F. Puentes, Br. J. Can. 74(5), 677 (1996) 174. A. Aiello, E. Fattorusso, M. Menna, R. Carnuccio, F. D'Acquisto, Tetrahedron 53, 5877-5882 (1997) 175. A. Aiello, E. Fattorusso, M. Menna, R. Carnuccio, T. Iuvone, Tetrahedron 53, 11489-11492 (1997) 176. C.L. Bromley, S. Parker-Nance, J.-A. de la Mare, A.L. Edkins, D.R. Beukes, M.T. Davies-Coleman, S. Afr. J. Chem. 66, 64-68 (2013) 177. A. Qureshi, D.J. Faulkner, Nat. Prod. Lett. 13(1), 59-62 (1999) 178. J. Sikorska, A.M. Hau, C. Anklin, S. Parker-Nance, M.T. Davies-Coleman, J.E. Ishmael, K.L. McPhail, J. Org. Chem. 77, 6066-6075 (2012) 179. K.E. Rudolph, M.S. Liberio, R.A. Davis, A.R. Carroll, Org. Biomol. Chem. 11, 261-270 (2012) 180. M. Kato, M. Sakai, K. Adachi, H. Ikemoto, H. Sano, Phytochemistry 42(5), 1341-1345 (1996) 181. K. Künzler, W. Eichenberger, Phytochemistry 46(5), 883-892 (1997) 182. A. Aiello, E. Fattorusso, A. Giordano, M. Menna, C. Navarrete, E. Munoz, Bioorg. Med. Chem. 15, 2920-2926 (2007) 183. A. Aiello, E. Fattorusso, A. Giordano, M. Menna, C. Navarrete, E. Munoz, Tetrahedron 65, 4384-4388 (2009) 184. M.J. Uddin, S. Kokubo, K. Suenaga, Heterocycles 54(2), 1039-1047 (2001) 185. M.J. Uddin, S. Kokubo, K. Ueda, K. Suenaga, D. Uemura, J. Nat. Prod. 64, 1169-1173 (2001) 186. M.J. Uddin, S. Kokubo, K. Ueda, K. Suenaga, D. Uemura, Chem. Lett. 10, 1028-1029 (2002) 187. M.J. Uddin, K. Ueda, E.R.O. Siwu, M. Kita, D. Uemura, Bioorg. Med. Chem. 14(20), 6954-6961 (2006) 188. X. Fu, M.B. Hossain, D. Van Der Helm, F.J. Schmitz, J. Am. Chem. Soc. 116, 12125-12126 (1994) 189. X. Fu, M.B. Hossain, F.J. Schmitz, D. vanderHelm, J. Org. Chem. 62, 3810-3819 (1997) 190. R.A. Davis, A.R. Carroll, R.J. Quinn, J. Nat. Prod. 62, 1405-1409 (1999) 191. X. Fu, M.L.G. Ferreira, F.J. Schmitz, J. Nat. Prod. 62, 1306-1310 (1999) 192. R.A. Davis, A.R. Carroll, R.J. Quinn, J. Nat. Prod. 62, 158-160 (1999) 193. H.H. Issa, J. Tanaka, R. Rachmat, T. Higa, Tetrahedron Lett. 44, 1243-1245 (2003) 194. S. De Rosa, A. Milone, A. Crispino, A. Jaklin, A. De Giulio, J. Nat. Prod. 60, 462-463 (1997) 195. N. Lindquist, W. Fenical, Tetrahedron Lett. 31(17), 2389-2392 (1990) 196. H. Kang, W. Fenical, Tetrahedron Lett. 37(14), 2369-2372 (1996) 197. S.A. Abas, M.B. Hossain, D. Van Der Helm, F.J. Schmitz, M. Laney, R. Cabuslay, R.C. Schatzman, J. Org. Chem. 61, 2709-2712 (1996) 198. M. Wessels, G.M. Konig, A.D. Wright, J. Nat. Prod. 64, 1556-1558 (2001) 199. W. Wang, T. Oda, A. Fujita, R.E.P. Mangindaan, T. Nakazawa, K. Ukai, H. Kobayashi, M. Namikoshi, Tetrahedron 63, 409-412 (2007) 200. C.D. Pham, H. Weber, R. Hartmann, V. Wray, W. Lin, D. Lai, P. Proksch, Org. Lett. 15, 2230-2233 (2013) 201. R. Takeara, P.C. Jimenez, D.V. Wilke, M.O. de Moraes, C. Pessoa, N.P. Lopes, J.L.C. Lopes, T.M.C. da Lotufo, L.V. Costa-Lotufo, Comp. Biochem. Physiol. 151, 363-369 (2008) 202. P.W. Ford, B.S. Davidson, J. Nat. Prod. 60(10), 1051-1053 (1997) 203. H. Niwa, M. Watanabe, H. Inagaki, K. Yamada, Tetrahedron 50(25), 7385-7400 (1994) 204. N.L. Segraves, S. Lopez, T.A. Johnson, S.A. Said, X. Fu, F.J. Schmitz, H. Pietraszkiewicz, F.A. Valeriote, P. Crews, Tetrahedron Lett. 44, 3471-3475 (2003) 205. N. Oku, S. Matsunaga, N. Fusetani, J. Am. Chem. Soc. 125, 2044-2045 (2003) 206. T. Ogi, P. Margiastuti, T. Teruya, J. Taira, K. Suenaga, K. Ueda, Mar. Drugs 7, 816-832 (2009) 207. T.N. Makarieva, A.S. Dmitrenok, P.S. Dmitrenok, B.B. Grebnev, V.A. Stonik, J. Nat. Prod. 64, 1559-1561 (2001) 208. P.J. Sung, M.-R. Lin, J.-J. Chen, S.-F. Lin, Y.-C. Wu, T.-L. Hwang, L.-S. Fang, Chem. Pharm. Bull. 55, 666-668 (2007) 209. Y. Miyata, T. Diyabalanage, C.D. Amsler, J.B. McClintock, F.A. Valeriote, B.J. Baker, J. Baker J. Nat. Prod. 70, 1859-1864 (2007) 210. H. Choi, H. Hwang, J. Chin, E. Kim, J. Lee, S.J. Nam, B.C. Lee, B.J. Rho, H. Kang, J. Nat. Prod. 74, 90-94 (2011) 211. T. Kusumi, Y. Shibata, M. Ishitsuka, T. Kinoshita, H. Kakisawa, Chem. Lett. 3, 277-278 (1979) 212. M. Segawa, H. Shirahama, Chem. Lett. 16(7), 1365-1366 (1987) 213. M.T. Davies-Coleman, C.L. Cantrell, K.R. Gustafson, J.A. Beutler, L.K. Pannell, M.R. Boyd, J. Nat. Prod. 63, 1411-1413 (2000) 214. V.K. Meenakshi, M. Paripooranaselvi, S. Sankaravadivoo, Int. J. Curr. Micro. Appl. Sci. 2(8), 286-295 (2013) 215. S. Urban, J.W. Blunt, M.H.G. Munro, J. Nat. Prod. 65, 1371-1373 (2002) 216. M. Kaneda, T. Naid, T. Kitahara, S. Nakamura, T. Hirata, T. Suga, J. Antibiot. 41(5), 602-608 (1998) 217. B.R. Copp, C.M. Wassvik, G. Lambert, M.J. Page, J. Nat. Prod. 63, 1168-1169 (2000) 218. N.B. Perry, J.W. Blunt, M.H.G. Munro, Aus. J. Chem. 44(4), 627-633 (1991) 219. M. Ishibashi, K. Deki, J.I. Kobayashi, J. Nat. Prod. 58(5), 804-806 (1995) 220. J. Kobayashi, K. Naitoh, Y. Doi, K. Deki, M. Ishibashi, J. Org. Chem. 60, 6941-6945 (1995) 221. A.J. Freyer, A.D. Patil, L. Killmer, N. Troupe, M. Mentzer, B. Carte, L. Faucette, R.K. Johnson, J. Nat. Prod. 60, 986-990 (1997) 222. B.S. Lindsay, C.N. Battershill, B.R. Copp, J. Nat. Prod. 61, 857-858 (1998) 223. S.S. Mitchell, D. Rhodes, F.D. Bushman, D.J. Faulkner, Org. Lett. 2, 1605-1607 (2000) 224. S. Yin, G.M. Boyle, A.R. Carroll, M. Kotiw, J. Dearnaley, R.J. Quinn, R.A. Davis, J. Nat. Prod. 73, 1586-1589 (2010) 225. A. Aiello, E. Fattorusso, C. Imperatore, C. Irace, P. Luciano, M. Menna, R. Santamaria, R. Vitalone, Mar. Drugs 9, 1157-1165 (2011) 226. C. Imperatore, A. Aiello, F. D'Aniello, P. Luciano, R. Vitalone, R. Meli, G.M. Raso, M. Menna, Molecules 17, 12642-12650 (2012) 227. A. Aiello, E. Fattorusso, C. Imperatore, M. Menna, W.E.G. Müller, Mar. Drugs 8, 285-291 (2010) 228. P. Ciminiello, C. Dell'Aversano, E. Fattorusso, S. Magno, M. Pansini, J. Nat. Prod. 63(2), 263-266 (2000) 229. M. Fujita, Y. Nakao, S. Matsunaga, T. Nishikawa, N. Fusetani, J. Nat. Prod. 65, 1936-1938 (2002) 230. J.A. Findlay, Z.Q. He, L.A. Calhoun, J. Nat. Prod. 53(4), 1015-1018 (1990) 231. F. Reyes, R. Fernandez, A. Rodríguez, A. Francesch, S. Taboada, C. Á vila, C. Cuevas, Tetrahedron 64, 5119-5123 (2008) 232. S. Kehraus, S. Gorzalka, C. Hallmen, J. Iqbal, C.E. Müller, A.D. Wright, M. Wiese, G.M. Konig, J. Med. Chem. 47, 2243-2255 (2004) 233. A. Aiello, S. Carbonelli, E. Fattorusso, T. Iuvone, M. Menna, J. Nat. Prod. 64, 219-221 (2001) 234. A. Simon-Levert, C. Menniti, L. Soulère, A.M. Genevière, C. Barthomeuf, B. Banaigs, A. Witczak, Mar. Drugs 8, 347-358 (2010) 235. A.R. Carroll, B.F. Bowden, J.C. Coll, Aus. J. Chem. 46(7), 1079-1083 (1993) 236. B.T. Murphy, S. Cao, P. Brodie, J. Maharavo, H. Andriamanantoanina, P. Ravelonandro, D.G.I. Kingston, J. Nat. Prod. 72, 1338-1340 (2009) 237. M.V.R. Reddy, D.J. Faulkner, Y. Venkateswarlu, M.R. Rao, Tetrahedron 53, 3457-3466 (1997) 238. A. Rudi, M. Aknin, E.M. Gaydou, Y. Kashman, Tetrahedron 54, 13203-13210 (1998) 239. Y. Nakamura, H. Kato, T. Nishikawa, N. Iwasaki, Y. Suwa, H. Rotinsulu, F. Losung, W. Maarisit, R.E.P. Mangindaan, H. Morioka, H. Yokosawa, S. Tsukamoto, Org. Lett. 15, 322-325 (2013) 240. K.L. Rinehart, Med. Res. Rev. 20(1), 1-27 (2000) 241. K.L. Rinehart, J.B. Gloer, R.G. Hughes, H.E. Renis, J.P. McGovren et al., Science 212(4497), 933-935 (1981) 242. M.B. Hossain, D. Van der Helm, J. Antel, G.M. Sheldrick, S.K. Sanduja, A.J. Weinheimer, PNAS 85(12), 4118-4122 (1988) 243. T.C. McKee, C.M. Ireland, N. Lindquist, W. Fenical, Tetrahedron lett. 30(23), 3053-3056 (1989) 244. W.R. Li, W.R. Ewing, B.D. Harris, M.M. Joullie, J. Am. Chem. Soc. 112(21), 7659-7672 (1990) 245. C.M. Crews, W.S. Lane, S.L. Schreiber, PNAS 93(9), 4316-4319 (1996) 246. L. Meng, N. Sin, C.M. Crews, Biochemistry 37(29), 10488-10492 (1998) 247. S. Weed, D.A. Stringfellow, Antivir. Res. 3, 269-274 (1983) 248. J. Urdiales, P. Morata, I.N. De Castro, F. Sanchez-Jiménez, Cancer Lett. 102(1), 31-37 (1996) 249. F.A. Dorr, J.G. Kuhn, J. Phillips, D.D. von Hoff, Eur. J. Can. Clin. Oncol. 24(11), 1699-1706 (1988) 250. W. Scheithauer, M.P. Moyer, G.M. Clark, D.D. Von Hoff, Can. Chem. Pharm. 21(1), 31-34 (1988) 251. D.W. Montgomery, C.F. Zukoski, Transplant 40(1), 49-56 (1985) 252. A.A. Geldof, S.C. Mastbergen, R.E. Henrar, G.T. Faircloth, Cancer Chem. Pharm. 44(4), 312-318 (1999) 253. J.A. Stewart, J.B. Low, J.D. Roberts, A. Blow, Cancer 68(12), 2550-2554 (1991) 254. D.M. Shin, P.Y. Holoye, W.K. Murphy, A. Forman, S.C. Papasozomenos, Cancer Chem. Pharm. 29(2), 145-149 (1991) 255. J.A. Benvenuto, R.A. Newman, G.S. Bignami, T.J.G. Raybould, M.N. Raber, L. Esparza, R.S. Walters, Invest. New Drugs 10(2), 113-117 (1992) 256. D.M. Shin, P.Y. Holoye, A. Forman, R. Winn, R. Perez-Soler, S. Dakhil et al., Invest. New Drugs 12(3), 243-249 (1994) 257. O. Kucuk, M.L. Young, T.M. Habermann, B.C. Wolf, J. Jimeno, P.A. Cassileth, Am. J. Clin. Oncol. 23(3), 273-277 (2000) 258. H. Hochster, R. Oratz, D.S. Ettinger, E. Borden, Invest. New Drugs 16(3), 259-263 (1998) 259. A. Mittelman, H.G. Chun, C. Puccio, N. Coombe, T. Lansen, T. Ahmed, Invest. New Drugs 17(2), 179-182 (1999) 260. S.A. Taylor, D.J. Giroux, K.A. Jaeckle, T.J. Panella, S.R. Dakhil, S.C. Schold, Invest. New Drugs 16(4), 331-332 (1998) 261. S. Ankisetty, S.I. Khan, B. Avula, D. Gochfeld, I.A. Khan, M. Slattery, Mar. Drugs 11(11), 4478-4486 (2013) 262. B. Nuijen, M. Bouma, R.E.C. Henrar, P. Floriano, J.M. Jimeno, H. Talsma et al., J. Pharm. Sci. Technol. 54(3), 193-208 (2000) 263. S. Donald, A. Gescher, J. Donaque, U.S. Patent Application 10/575,132; 2004 264. S. Donald, R.D. Verschoyle, P. Greaves, T.W. Gant, T. Colombo, M. Zaffaroni et al., Cancer Res. 63, 5903-5908 (2003) 265. J.H. Beumer, J.H. Schellen, J.H. Beijnen, Pharm. Res. 51, 391-398 (2005) 266. K.L. Rinehart, A.M. Lithgow-Bertelloni, PCT Int. Pat. Appl. WO 91, 04985 (1991) 267. L.F. Garcia-Fernandez, A. Losada, V. Alcaide, A.M. Alvarez, A. Cuadrado, K.I. Nakayama, J.M. Fernandez-Sousa, A. Munoz, J.M. Sanchez-Puelles, Oncogene 21, 7533-7544 (2002) 268. C. Gajate, F. An, F. Mollinedo, Clin. Cancer Res. 9, 1535-1545 (2003) 269. D.R. Grubb, J.D. Ly, F. Vaillant, K.L. Johnson, A. Lawen, Oncogene 20, 4085-4094 (2001) 270. A. Cuadrado, L.F. García-Fernandez, L. Gonzalez, Y. Suarez, A. Losada, V. Alcaide, T. Martinez, J. Fernandez-Sousa, J.M. Sanchez-Puelles, A. Munoz, J. Biol. Chem. 278(1), 241-250 (2003) 271. A. Cuadrado, L. Gonzalez, Y. Suarez, T. Martinez, A. Munoz, Oncogene 23, 4673-4680 (2004) 272. M. Broggini, S.V. Marchini, E. Galliera, P. Borsotti, G. Taraboletti, E. Erba, M. Sironi, J. Jimeno, G.T. Faircloth, R. Giavazzi, M. D'Incalci, Leukemia 7, 52-59 (2003) 273. M. Biscardi, R. Caporale, F. Balestri, S. Gavazzi, J. Jimeno, A. Grossi, Ann. Oncol. 16(10), 1667-1674 (2005) 274. A. Losada, J.M. Lopez-Oliva, J.M. Sanchez-Puelles, L.F. Garcia-Fernandez, Br. J. Cancer 91, 1405-1413 (2004) 275. E. Erba, M. Serafini, G. Gaipa, G. Tognon, S. Marchini, N. Celli, D. Rotilio, M. Broggini, J. Jimeno, G.T. Faircloth, A. Biondi, M. D'Incalci, Br. J. Cancer 89, 763-773 (2003) 276. B. Albella, G. Faircloth, L. Lopez-Lazaro, C. Guzman, J. Jimeno, J.A. Bueren, Eur. J. Cancer 38, 1395-1404 (2002) 277. M.A. Baker, D.R. Grubb, A. Lawen, Apoptosis 7, 407-412 (2002) 278. T. Fischer, R.M. Stone, D.J. DeAngelo, I. Galinsky, E. Estey, C. Lanza, E. Fox, G. Ehninger, E.J. Feldman, G.J. Schiller, V.M. Klimek, S.D. Nimer, D.G. Gilliland, C. Dutreix, A. HuntsmanLabed, J. Virkus, F.J. Giles, J. Clin. Oncol. 28(28), 4339-4345 (2010) 279. M.J. Millward, C. House, D. Bowtell, L. Webster, I.N. Olver, M. Gore, M. Copeman, K. Lynch, A. Yap, Y. Wang, P.S. Cohen, J. Zalcberg, Br. J. Cancer 95, 829-834 (2006) 280. S. Knapper, A.K. Burnett, T. Littlewood, W.J. Kell, S. Agrawal, R. Chopra, R. Clark, M.J. Levis, D. Small, Blood 108(10), 3262-3270 (2006) 281. E.O. Hexner, C. Serdikoff, M. Jan, C.R. Swider, C. Robinson, S. Yang, T. Angeles, S.G. Emerson, M. Carroll, B. Ruggeri, P. Dobrzanski, Blood 111(12), 5663-5671 (2008) 282. R.B. Kinnel, P.J. Scheuer, J. Org. Chem. 57(23), 6327-6329 (1992) 283. S. Sato, N. Fujita, T. Tsuruo, Oncogene 21(11), 1727-1738 (2002) 284. R.T. Bunch, A. Eastman, Clin. Cancer Res. 2(5), 791-797 (1996) 285. I. Takahashi, K. Asano, I. Kawamoto, T. Tamaoki, H. Nakano, J. Antibiot. 42(4), 564-570 (1989) 286. S.J. Hotte, A. Oza, E.W. Winquist, M. Moore, E.X. Chen, S. Brown, G.R. Pond, J.E. Dancey, H.W. Hirte, Ann. Oncol. 17(2), 334-340 (2006) 287. C.X. Ma, M.J. Ellis, G.R. Petroni, Z. Guo, S.R. Cai, C.E. Ryan et al., Br. Can. Res. Treat. 137(2), 483-492 (2013) 288. H. Zhao, J.L. Watkins, H. Piwnica-Worms, PNAS 99(23), 14795-14800 (2002) 289. D. Komander, G. Kular, J. Bain, M. Elliott, D. Alessi, D. Vanaalten, Biochemistry 375, 255-262 (2003) 290. X. Jiang, B. Zhao, R. Britton, L.Y. Lim, D. Leong, J.S. Sanghera, B.B. Zhou, E. Piers, R.J. Andersen, M. Roberge, Mol. Cancer. Ther. 3(10), 1221-1227 (2004) 291. C.J. Nock, J.M. Brell, J.A. Bokar, M.M. Cooney, B. Cooper, J. Gibbons, S. Krishnamurthi, S. Manda, P. Savvides, S.C. Remick, P. Ivy, A. Dowlati, Invest. New Drugs 29(1), 126-130 (2011) 292. A. Schwandt, T. Mekhail, B. Halmos, T. O'Brien, P.C. Ma, P. Fu, P. Ivy, A. Dowlati, J. Thora, Oncology 7(4), 751 (2012) 293. P. Bhargava, J. Marshall, W. Dahut, N. Rizvi, M. Dordal, E. Samar, T. Elshourbagy, E. Ness, J. Bischoff, M. Hawkins, Ann. Oncol. 9, 424 (1998) 294. S.D. Undevia, N.J. Vogelzang, A.M. Mauer, L. Janisch, S. Mani, M.J. Ratain, Invest. New Drugs 22(4), 449-458 (2004) 295. A.C. Maroney, J.P. Finn, T.J. Connors, J.T. Durkin, T. Angeles, G. Gessner, Z. Xu, S.L. Meyer, M.J. Savage, L.A. Greene, R.W. Scott, J.L. Vaught, J. Biol. Chem. 276(27), 25302-25308 (2001) 296. C.A. Harris, M. Deshmukh, B. TsuiPierchala, A.C. Maroney, E.M. Johnson Jr., J. Neurosci. 22(1), 103-113 (2002) 297. M.S. Saporito, E.M. Brown, M.S. Miller, S. Carswell, J. Pharm. Exp. Ther. 288(2), 421-427 (1999) 298. M.S. Saporito, R.L. Hudkins, A.C. Maroney, Prog. Med. Chem. 40, 23-62 (2002) 299. Z.K. Sweeney, J.W. Lewcock, A.C.S. Chem, Neurology 2(1), 3-4 (2010) 300. M.W. Karaman, S. Herrgard, D.K. Treiber, P. Gallant, C.E. Atteridge, B.T. Campbell, K.W. Chan, P. Ciceri, M.I. Davis, P.T. Edeen, R. Faraoni, M. Floyd, J.P. Hunt, D.J. Lockhart, Z.V. Milanov, M.J. Morrison, G. Pallares, H.K. Patel, S. Pritchard, L.M. Wodicka, P.P. Zarrinkar, Nat. Biotechnol. 26(1), 127-132 (2008) 301. T. Tamoki, H. Nomoto, I. Takahashi, Y. Kato, M. Morimoto, F. Tomita, Biochem. Biophys. Res. Commun. 135, 397-402 (1986) 302. D. Tanramluk, A. Schreyer, W.R. Pitt, T.L. Blundell, Chem. Boil. Drug Des. 74(1), 16-24 (2009) 303. F. Meggio, A.D. Deana, M. Ruzzene, A.M. Brunati, L. Cesaro, B. Guerra, T. Meyer, H. Mett, D. Fabbro, P. Furet et al., Eur. J. Biochem. 234(1), 317-322 (1995) 304. I. Kruman, Q. Guo, J. Neurosci. Res. 51(3), 293-308 (1998) 305. D. Tang, V.J. Kidd, J. Biol. Chem. 44, 28549-28552 (1998) 306. A.C. Johansson, H. Steen, K. O llinger, K. Roberg, Cell. Death Differ. 10(11), 1253-1259 (2003) 307. J. Manns, M. Daubrawa, S. Driessen, F. Paasch, N. Hoffman, A. Loffler, K. Lauber, A. Dieterle, S. Alers, T. Iftner, K. SchulzeOsthoff, B. Stork, S. Wesselborg, FASEB J. 25(9), 3250-3261 (2011) 308. G. Li, A. Gleinich, H. Lau, M. Zimmermann, Neurochem. Int. 61(7), 1011-1020 (2012) 309. M. Halabalaki, K. Vougogiannopoulou, E. Mikros, A.L. Skaltsounis, Curr. Opin. Biotechnol. 25, 1-7 (2014) 310. T.F. Molinski, Nat. Prod. Rep. 27(3), 321-329 (2010) 311. L. Mannina, A.P. Sobolev, S. Viel, Progr. Nucl. Mag. Reson. Spect. 66, 1-39 (2012) 312. B. Vogler, I. Klaiber, G. Roos, C.U. Walter, W. Hiller, P. Sandor, W. Kraus, J. Nat. Prod. 61(2), 175-178 (1998) 313. V. Exarchou, M. Krucker, T.A. van Beek, J. Vervoort, I.P. Gerothanassis, K. Albert, Mag. Reson. Chem. 43(9), 681-687 (2005) 314. D.J. Crockford, H.C. Keun, L.M. Smith, E. Holmes, J.K. Nicholson, Anal. Chem. 77(14), 4556-4562 (2005) 315. A.D. Maher, J.M. Fonville, M. Coen, J.C. Lindon, C.D. Rae, J.K. Nicholson, Anal. Chem. 84(2), 1083-1091 (2011) 316. J.M. Posma, I. Garcia-Perez, M. De Iorio, J.C. Lindon, P. Elliott, E. Holmes, T.M. Ebbels, J.K. Nicholson, Anal. Chem. 84(24), 10694-10701 (2012) 317. S.L. Robinette, R. Bruschweiler, F.C. Schroeder, A.S. Edison, Acc. Chem. Res. 45, 288-297 (2012) 318. M. Pascolutti, M. Campitelli, B. Nguyen, N. Pham, A.D. Gorse, R.J. Quinn, PLoS ONE 10(4), e0120942 (2015) 319. J.L. Stark, R. Powers, Application of NMR and molecular docking in structure-based drug discovery, in NMR of Proteins and Small Biomolecules, ed. by k Chen, N. Tjandra (Springer, Berlin, 2012), pp. 1-34 320. J.G. Napolitano, D.C. Lankin, T.N. Graf, J.B. Friesen, S.N. Chen, J.B. McAlpine, N.H. Oberlies, G.F. Pauli, J. Org. Chem. 78(7), 2827-2839 (2013) 321. M. Elyashberg, K. Blinov, S. Molodtsov, A.J. Williams, J. Nat, Production 76(1), 113-116 (2013) 322. M. Elyashberg, A.J. Williams, K. Blinov, Nat. Prod. Rep. 27(9), 1296-1328 (2010) 323. B. Plainchont, J.M. Nuzillard, Magn. Reson. Chem. 51(1), 54-59 (2013) 324. J.L. López-Pérez, R. Therón, E. del Olmo, D. Díaz, Bioinformatics 23(23), 3256-3257 (2007) 325. K. Bingol, F. Zhang, L. Bruschweiler-Li, R. Brüschweiler, Anal. Chem. 84(21), 9395-9401 (2002) 326. J. Blunt, M. Munro, M. Upjohn, The role of databases in marine natural products research, in Handbook of Marine Natural Products, ed. by E. Fattorusso, W.H. Gerwick, O. TaglialatelaScafati (Springer, Rotterdam, 2012), pp. 389-421 327. M. Spraul, B. Schütz, E. Humpfer, M. Mortter, H. Schäfer, S. Koswig, P. Rinke, Mag. Reson. Chem. 47(S1), S130-S137 (2009) 328. B. Zhou, J.F. Xiao, L. Tuli, H.W. Ressom, Mol. Biosyst. 8(2), 470-481 (2012) 329. C. Kuhlisch, G. Pohnert, Nat. Prod. Rep. 32(7), 937-955 (2015) 330. H.K. Kim, Y.H. Choi, R. Verpoorte, Nat. Protoc. 5(3), 536-549 (2010) 331. H.K. Kim, Y.H. Choi, R. Verpoorte, Trend Biotechnol. 29(6), 267-275 (2011) 332. A.P. Tikunov, C.B. Johnson, H. Lee, M.K. Stoskopf, J.M. Macdonald, Mar. Drugs 8(10), 2578-2596 (2010) 333. H. Wu, X. Liu, J. Zhao, J. Yu, Mar. Drugs 9(9), 1566-1579 (2011) 334. E.M. Sogin, P. Anderson, P. Williams, C.S. Chen, R.D. Gates, PLoS ONE 9(10), e111274 (2014) 335. U. Bose, A.K. Hewavitharana, Y.K. Ng, P.N. Shaw, J.A. Fuerst, M.P. Hodson, Mar. Drugs 13(1), 249-266 (2015) 336. S. Halouska, R.J. Fenton, R.G. Barletta, R. Powers, ACS Chem. Boil. 7(1), 166-171 (2012) 337. S. Goulitquer, P. Potin, T. Tonon, Mar. Drugs 10(4), 849-880 (2013) 338. N.G. Mahieu, J.L. Genenbacher, G.J. Patti, Curr. Opin. Chem. Biol. 30, 87-93 (2016) 339. Q. Cheng, L. Xiang, M. Izumikawa, D. Meluzzi, B.S. Moore, Nat. Chem. Biol. 3, 557-558 (2007) 340. S.K. Palanisamy, D. Trisciuoglio, C. Zwergel, D. Del Bufalo, A. Mai, J. Enzyme Inhib. Med. Chem. (2016). doi:10.1080/14756366.2016.1266344 341. S.K. Palanisamy, R. Morabito, A. Remigante, N. Spano, G. La Spada, S. Giacobbe, A. Marino, J. Biol, Research 89(5812), 27-32 (2016) 342. K.F. Chater, D.A. Hopwood, Genet. Bact. Divers. 3, 129-150 (1989) 343. M.S. Donia, J. Ravel, E.W. Schmidt, Nat. Chem. Biol. 4(6), 341 (2008) 344. M.D.B. Tianero, J.C. Kwan, T.P. Wyche, A.P. Presson, M. Koch, L.R. Barrows, T.S. Bugni, E.W. Schmidt, ISME J. 9(3), 615-628 (2015)

[1]	Patricia Quintero-Rincón, Karina Caballero-Gallardo, Jesus Olivero-Verbel. Natural anticancer agents: prospection of medicinal and aromatic plants in modern chemoprevention and chemotherapy[J]. 应用天然产物, 2025, 15(3): 25-25.
[2]	Pengkun Li, Qin Li, Aimin Fu, Yang Xiao, Chunmei Chen, Hucheng Zhu, Changxing Qi, Wei Wei, Yuan Zhou, Yonghui Zhang. Emestrin-type epipolythiodioxopiperazines from Aspergillus nidulans with cytotoxic activities by regulating PI3K/AKT and mitochondrial apoptotic pathways[J]. 应用天然产物, 2025, 15(2): 17-17.
[3]	Olusesan Ojo, Idris Njanje, Dele Abdissa, Tarryn Swart, Roxanne L. Higgitt, Rosemary A. Dorrington. Newly isolated terpenoids (covering 2019-2024) from Aspergillus species and their potential for the discovery of novel antimicrobials[J]. 应用天然产物, 2025, 15(2): 19-19.
[4]	Hesham R. El-Seedi, Mohamed S. Refaey, Nizar Elias, Mohamed F. El-Mallah, Faisal M. K. Albaqami, Ismail Dergaa, Ming Du, Mohamed F. Salem, Haroon Elrasheid Tahir, Maria Dagliaa, Nermeen Yosri, Hongcheng Zhang, Awg H. El-Seedi, Zhiming Guo, Shaden A. M. Khalifa. Marine natural products as a source of novel anticancer drugs: an updated review (2019-2023)[J]. 应用天然产物, 2025, 15(2): 13-13.
[5]	Dong-Yang Wang, Ming-Xing Li, Yan-Chao Xu, Peng Fu, Wei-Ming Zhu, Li-Ping Wang. Dibohemamines I-O from Streptomyces sp. GZWMJZ-662, an endophytic actinomycete from the medicinal and edible plant Houttuynia cordata Thunb.[J]. 应用天然产物, 2025, 15(1): 9-9.
[6]	Jiaojiao Ji, Lanlan Zang, Tingting Lu, Cheng Li, Xiaoxu Han, Soo-Rang Lee, Li Wang. Widely targeted metabolomics analysis reveals differences in volatile metabolites among four Angelica species[J]. 应用天然产物, 2025, 15(1): 2-2.
[7]	Yue-Mei Chen, Nan-Kai Cao, Si-Si Zhu, Meng Ding, Hai-Zhen Liang, Ming-Bo Zhao, Ke-Wu Zeng, Peng-Fei Tu, Yong Jiang. Euchrestifolines A-O, fifteen novel carbazole alkaloids with potent anti-ferroptotic activity from Murraya euchrestifolia[J]. 应用天然产物, 2025, 15(1): 5-5.
[8]	Alica Fischle, Mika Lutsch, Florian Hübner, Linda Sch?ker-Hübner, Lina Schürmann, Finn K. Hansen, Svetlana A. Kalinina. Micro-scale screening of genetically modified Fusarium fujikuroi strain extends the apicidin family[J]. 应用天然产物, 2024, 14(6): 51-51.
[9]	Yuru Shi, Xiaoqian Zhang, Shengji Pei, Yuhua Wang. Ethnopharmacological study on Adenosma buchneroides Bonati inhibiting inflammation via the regulation of TLR4/MyD88/NF-κB signaling pathway[J]. 应用天然产物, 2024, 14(5): 36-36.
[10]	Qi-Xiu Hai, Kun Hu, Su-Ping Chen, Yang-Yang Fu, Xiao-Nian Li, Han-Dong Sun, Hong-Ping He, Pema-Tenzin Puno. Silvaticusins A-D: ent-kaurane diterpenoids and a cyclobutane-containing ent-kaurane dimer from Isodon silvaticus[J]. 应用天然产物, 2024, 14(5): 45-45.
[11]	Ismail Ware, Katrin Franke, Andrej Frolov, Kseniia Bureiko, Elana Kysil, Maizatulakmal Yahayu, Hesham Ali El Enshasy, Ludger A. Wessjohann. Comparative metabolite analysis of Piper sarmentosum organs approached by LC-MS-based metabolic profiling[J]. 应用天然产物, 2024, 14(4): 30-30.
[12]	Antonio Evidente. Advances on anticancer fungal metabolites: sources, chemical and biological activities in the last decade (2012-2023)[J]. 应用天然产物, 2024, 14(4): 31-31.
[13]	Guifeng Su, Dan Wang, Qianqing Yang, Lingmei Kong, Xiaoman Ju, Qihong Yang, Yiying Zhu, Shaohua Zhang, Yan Li. Cepharanthine suppresses APC-mutant colorectal cancers by down-regulating the expression of β-catenin[J]. 应用天然产物, 2024, 14(2): 6-6.
[14]	Shiyun Nie, Lizhong Chang, Ying Huang, Heyang Zhou, Qianqing Yang, Lingmei Kong, Yan Li. β-carboline derivative Z86 attenuates colorectal cancer cell proliferation and migration by directly targeting PI3K[J]. 应用天然产物, 2024, 14(1): 3-3.
[15]	Kritika Jalota, Vikas Sharma, Chiti Agarwal, Suruchi Jindal. Eco-friendly approaches to phytochemical production: elicitation and beyond[J]. 应用天然产物, 2024, 14(1): 5-5.