Bioactive Heterocyclic Alkaloids of Marine Origin

  • Masaki Kita
  • Daisuke UemuraEmail author
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 6)


Many kinds of alkaloids with extraordinary structures and significant biological activities have been isolated from marine organisms. This work features the structures, biological activities, and biogenesis of novel heterocyclic marine alkaloids, which control biologically and physiologically intriguing phenomena. Pinnatoxins and pteriatoxins, potent shellfish poisons, were isolated from the Okinawan bivalve Pinna sp. and Pteria sp. Norzoanthamine hydrochloride, isolated from the colonial zoanthid Zoanthus sp., suppresses decreases in bone weight and strength in ovariectomized mice. Symbioimine, an amphoteric iminium metabolite from the dinoflagellate Symbiodinium sp., inhibits osteoclast differentiation. Other novel alkaloids, such as pinnamine, pinnaic acids, halichlorine, and zamamistatin, are also described.

Heterocyclic marine alkaloids Shellfish poison Anti-osteoporosis Super-carbon-chain compound 


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  1. 1.
    Kuramoto M, Arimoto H, Uemura D (2003) Studies in bioactive marine alkaloids. J Synth Org Chem Jpn 61:1099 Google Scholar
  2. 2.
    Kuramoto M, Arimoto H, Uemura D (2004) Bioactive marine alkaloids. A review. Mar Drugs 1:39 CrossRefGoogle Scholar
  3. 3.
    Gerwick WH, Tan LT, Sitachitta N (2001) Alkaloids of marine cyanobacteria. In: Cordell GA (ed) The Alkaloids, vol 57. Academic Press, San Diego, p 75 Google Scholar
  4. 4.
    Fusetani N, Matsunaga S (1993) Bioactive sponge peptides. Chem Rev 93:1793 CrossRefGoogle Scholar
  5. 5.
    Shimizu Y (1993) Microalgal metabolites. Chem Rev 93:1685 CrossRefGoogle Scholar
  6. 6.
    Shimizu Y (1996) Microalgal metabolites: A new perspective. Annu Rev Microbiol 50:431 CrossRefGoogle Scholar
  7. 7.
    Daranas AH, Norte M, Fernández JJ (2001) Toxic marine microalgae. Toxicon 39:1101 CrossRefGoogle Scholar
  8. 8.
    Rosewater J (1961) The family Pinnidae in the Indo-Pacific. Indo-Pacific Mollusca 1:53/501/632 Google Scholar
  9. 9.
    Zheng SZ, Huang FL, Chen SC, Tan XF, Zuo JB, Peng J, Xie RW (1990) The Isolation and bioactivities of pinnatoxin. Zhongguo Haiyang Yaowu (Chinese Journal of Marine Drugs) 9:33 Google Scholar
  10. 10.
    Uemura D, Chou T, Haino T, Nagatsu A, Fukuzawa S, Zheng SZ, Chen H (1995) Pinnatoxin A: a toxic amphoteric macrocycle from the Okinawan bivalve Pinna muricata. J Am Chem Soc 117:1155 CrossRefGoogle Scholar
  11. 11.
    Chou T, Kamo O, Uemura D (1996a) Relative stereochemistry of pinnatoxin A, a potent shellfish poison from Pinna muricata. Tetrahedron Lett 37:4023 CrossRefGoogle Scholar
  12. 12.
    Chou T, Haino T, Kuramoto M, Uemura D (1996c) Isolation and structure of pinnatoxin D, a new shellfish poison from the Okinawan bivalve Pinna muricata. Tetrahedron Lett 37:4027 CrossRefGoogle Scholar
  13. 13.
    Takada N, Uemura N, Suenaga K, Chou T, Nagatsu A, Haino T, Yamada K, Uemura D (2001a) Pinnatoxins B and C, the most toxic components in the pinnatoxin series from the Okinawan bivalve Pinna muricata. Tetrahedron Lett 42:3491 CrossRefGoogle Scholar
  14. 14.
    McCauley JA, Nagasawa K, Lander PA, Mischke SG, Semones MA, Kishi Y (1998) Total synthesis of pinnatoxin A. J Am Chem Soc 120:7647 CrossRefGoogle Scholar
  15. 15.
    Nagasawa K (2000) Total synthesis of pinnatoxin A. J Synth Org Chem Jpn 58:877 Google Scholar
  16. 16.
    Takada N, Uemura N, Suenaga K, Uemura D (2001b) Structural determination of pteriatoxins A, B and C, extremely potent toxins from the bivalve Pteria penguin. Tetrahedron Lett 42:3495 CrossRefGoogle Scholar
  17. 17.
    Takada N, Iwatsuki M, Suenaga K, Uemura D (2000) Pinnamine, an alkaloidal marine toxin, isolated from Pinna muricata. Tetrahedron Lett 41:6425 CrossRefGoogle Scholar
  18. 18.
    Djerassi C, Records R, Bunnenberg E, Mislow K, Miscowitz A (1962) Inherently dissymetric chromophores. Optical rotatory dispersion of α,β-unsaturated ketones and conformational analysis of cyclohexenones. J Am Chem Soc 84:870 CrossRefGoogle Scholar
  19. 19.
    Carmichael WW, Blggs DF, Gorham PR (1975) Toxicology and pharmacological action of anabaena flos-aquae toxin. Science 187:542 CrossRefGoogle Scholar
  20. 20.
    Devlin JP, Edwards OE, Gorham PR, Hunter NR, Pike RK, Stavric B (1977) Anatoxin A, a toxic alkaloid from anabaena-flos-aquae NRC-44H. Can J Chem 55:1367 CrossRefGoogle Scholar
  21. 21.
    Leete E, Marion L, Spenser ID (1954) The biogenesis of alkaloids. 12. The mode of formation of the tropine base of hyoscyamine. Can J Chem 32:1116 CrossRefGoogle Scholar
  22. 22.
    Kigoshi H, Hayashi N, Uemura D (2001) Stereoselective synthesis of pinnamine, an alkaloidal marine toxin from Pinna muricata. Tetrahedron Lett 42:7469 CrossRefGoogle Scholar
  23. 23.
    Fukuzawa S, Hayashi Y, Uemura D, Nagastu A, Yamada K, Ijyuin Y (1995) The isolation and structures of five new alkaloids, norzoanthamine, oxyzoanthamine, norzoanthaminone, cyclozoanthamine and epinorzoanthamine. Heterocycl Commun 1:207 Google Scholar
  24. 24.
    Rao CB, Anjaneyula ASR, Sarma NS, Venkatateswarlu Y, Rosser RM, Faulkner DJ, Chen MHM, Clardy J (1984) Zoanthamine; a novel alkaloid from a marine zoanthid. J Am Chem Soc 106:7983 CrossRefGoogle Scholar
  25. 25.
    Rao CB, Anjaneyula ASR, Sarma NS, Venkatateswarlu Y, Rosser RM, Faulkner DJ, Chen MHM, Clardy J (1985) Alkaloids from a marine zoanthid. J Org Chem 50:3757 CrossRefGoogle Scholar
  26. 26.
    Rahman AU, Alvi KA, Abbas SA, Choudhary MI, Clardy J (1989) Zoanthaminone, a new alkaloid from a marine zoanthid. Tetrahedron Lett 30:6825 CrossRefGoogle Scholar
  27. 27.
    Kuramoto M, Hayashi K, Fujitani Y, Yamaguchi K, Tsuji T, Yamada K, Ijyuin Y, Uemura D (1997) Absolute configuration of norzoanthamine, a promising candidate for an osteoporotic drug. Tetrahedron Lett 38:5683 CrossRefGoogle Scholar
  28. 28.
    Nakamura H, Kawase Y, Maruyama K, Murai A (1998) Studies on polyketide metabolites of a symbiotic dinoflagellate, Symbiodinium sp: A new C30 marine alkaloid, zooxanthellamine, a plausible precursor for zoanthid alkaloids. Bull Chem Soc Jpn 71:781 CrossRefGoogle Scholar
  29. 29.
    Kuramoto M, Hayashi K, Yamaguchi K, Yada M, Tsuji T, Uemura D (1998) Structure-activity relationship of norzoanthamine exhibiting significant inhibition of osteoporosis. Bull Chem Soc Jpn 71:771 CrossRefGoogle Scholar
  30. 30.
    Yamaguchi K, Hayama T, Makita T, Tsuji T (1997) Time course of bone biomechanical parameters in ovariectomized mice. J Bone Miner Metab 15:138 CrossRefGoogle Scholar
  31. 31.
    Kuramoto M, Yamaguchi K, Tsuji T, Uemura D (2000) Zoanthamines, antiosteoporotic alkaloids. In: Fusetani N (ed) Drugs from the Sea. Karger, Basel, p 98 CrossRefGoogle Scholar
  32. 32.
    Kuiper GGJM, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson J (1996) Cloning of a novel estrogen receptor expressed in rat prostate and ovary. Proc Natl Acad Sci USA 93:5925 CrossRefGoogle Scholar
  33. 33.
    Turner CH, Burr DB (1993) Basic biomechanical measurements of bone: A tutorial. Bone 14:595 CrossRefGoogle Scholar
  34. 34.
    Ducy P, Desbois C, Boyce B, Pinero G, Story B, Dunstan C, Smith E, Bonadio J, Goldstein S, Gundberg C, Bradley A, Karsenty G (1996) Increased bone formation in osteocalcin-deficient mice. Nature 382:448 CrossRefGoogle Scholar
  35. 35.
    Miyashita M, Sasaki M, Hattori I, Sakai M, Tanino K (2004) Total synthesis of norzoanthamine. Science 305:495 CrossRefGoogle Scholar
  36. 36.
    van den Bosch H (1980) Intracellular phospholipases A. Biochim Biophys Acta 604:191 CrossRefGoogle Scholar
  37. 37.
    Arita H, Nakano T, Hanasaki K (1989) Thromboxane A2: its generation and role in platelet activation. Prog Lipid Res 28:273 CrossRefGoogle Scholar
  38. 38.
    Scheuer PJ, de Silva ED (1980) Manoalide, an antibiotic sesterterpenoid from the marine sponge Luffariella variabilis (polejaeff). Tetrahedron Lett 21:1611 CrossRefGoogle Scholar
  39. 39.
    Albizati KF, Holman T, Faulkner DJ, Glaser KB, Jacobs RS (1987) Luffariellolide, an anti-infmammatory sesterterpene from the marine sponge Luffariella sp. Experientia 43:949 CrossRefGoogle Scholar
  40. 40.
    Potts BCM, Faulkner DJ, de Carvalho MS, Jacobs RS (1992a) Chemical mechanism of inactivation of bee venom phospholipase A2 by the marine natural products manoalide, luffariellolide, and scalaradial. J Am Chem Soc 114:5093 CrossRefGoogle Scholar
  41. 41.
    Potts BCM, Faulkner DJ, Jacobs RS (1992b) Phospholipase A2 inhibitors from marine organisms. J Nat Prod 66:1701 CrossRefGoogle Scholar
  42. 42.
    Kim DK, Kudo I, Fujimori Y, Mizushima H, Masuda M, Kikuchi R, Ikizawa K, Inoue K (1990) Detection and subcellular localization of rabbit platelet phospholipase A2 which preferentially hydrolyzes an arachidonoyl residue. J Biochem 108:903 Google Scholar
  43. 43.
    Kramer RM, Johansen B, Hession C, Pepinsky RB (1990) Structure and properties of a secretable phospholipase A2 from human platelets. Adv Exp Med Biol 275:35 Google Scholar
  44. 44.
    Kramer RM, Sharp JD (1995) Recent insights into the structure, function and biology of cPLA2. Agents Actions Suppl 46:65 Google Scholar
  45. 45.
    Chou T, Kuramoto M, Otani Y, Shikano M, Yazawa K, Uemura D (1996b) Pinnaic acid and tauropinnaic acid: two novel fatty acids composing a 6-azaspiro[4.5]decane unit from the Okinawan bivalve Pinna muricata. Tetrahedron Lett 37:3871 CrossRefGoogle Scholar
  46. 46.
    Kock AE, Halloran MM, Haskell CJ, Sah MR, Polverini PJ (1995) Angiogenesis mediated by soluble forms of E-selectin and vascular cell adhesion molecule-1. Nature 376:517 CrossRefGoogle Scholar
  47. 47.
    Osborn L, Hession C, Tizard R, Vassallo C, Huhovoskyi S, Chi-Rosso G, Hobb R (1988) Direct expression cloning of vascular cell adhesion molecule 1: a cytokine-induced endothelial protein that binds to lymphocytes. Cell 59:1203 CrossRefGoogle Scholar
  48. 48.
    Kuramoto M, Chou T, Yamada K, Chiba T, Hayashi Y, Uemura D (1996) Halichlorine, an inhibitor of VCAM-1 induction from the marine sponge Halichondria okadai Kadota. Tetrahedron Lett 37:3867 CrossRefGoogle Scholar
  49. 49.
    Arimoto H, Hayakawa I, Kuramoto M, Uemura D (1998) Absolute stereochemistry of halichlorine; a potent inhibitor of VCAM-1 induction. Tetrahedron Lett 39:861 CrossRefGoogle Scholar
  50. 50.
    Clive DLJ, Yu M, Wang J, Yeh VSC, Kang S (2005) Synthetic chemistry of halichlorine and the pinnaic acids. Chem Rev 105:4483 CrossRefGoogle Scholar
  51. 51.
    Carson MW, Kim G, Hentemann MF, Trauner D, Danishefsky SJ (2001) Concise stereoselective routes to advanced intermediates related to natural and unnatural pinnaic acid. Angew Chem Int Ed 40:4450 CrossRefGoogle Scholar
  52. 52.
    Carson MW, Kim G, Danishefsky SJ (2001) Stereochemistry of natural and unnatural pinnaic acids: a remarkable long-range stereochemical effect in the reduction of 17-oxo precursors of the pinnaic acids. Angew Chem Int Ed 40:4453 CrossRefGoogle Scholar
  53. 53.
    Trauner D, Danishefsky SJ (1999) Studies towards the total synthesis of halichlorine: asymmetric synthesis of the spiroquinolizidine subunit. Tetrahedron Lett 40:6513 CrossRefGoogle Scholar
  54. 54.
    Trauner D, Schwarz JB, Danishefsky SJ (1999) Total synthesis of (+)-halichlorine: an inhibitor of VCAM-1 expression. Angew Chem Int Ed 38:3542 CrossRefGoogle Scholar
  55. 55.
    Hayakawa I, Arimoto H, Uemura D (2003) Synthesis of (+)-pinnaic acid. Heterocycles 59:441 CrossRefGoogle Scholar
  56. 56.
    Bhadury P, Wright PC (2004) Exploitation of marine algae: biogenic compounds for potential antifouling applications. Planta 219:561 CrossRefGoogle Scholar
  57. 57.
    Yamada A, Kitamura H, Yamaguchi K, Fukuzawa S, Kamijima C, Yazawa K, Kuramoto M, Wang GYS, Fujitani Y, Uemura D (1997) Development of chemical substances regulating biofilm formation. Bull Chem Soc Jpn 70:3061 CrossRefGoogle Scholar
  58. 58.
    Takada N, Watanabe R, Suenaga K, Yamada K, Ueda K, Kita M, Uemura D (2001) Zamamistatin, a significant antibacterial bromotyrosine derivative, from the Okinawan sponge Pseudoceratina purpurea. Tetrahedron Lett 42:5265 CrossRefGoogle Scholar
  59. 59.
    Moody K, Thomson RH, Fattorusso E, Minale L, Sodano G (1972) Aerothionin and homoaerothionin: two tetrabromo spirocyclohexadienylisoxazoles from Verongia sponges. J Chem Soc Perkin Trans 1, p 18 Google Scholar
  60. 60.
    Ogamino T, Obata R, Nishiyama S (2006) Symmetric synthesis of aerothionin, a marine dimeric spiroisoxazoline natural product, employing optically active spiroisoxazoline derivative. Tetrahedron Lett 47:727 CrossRefGoogle Scholar
  61. 61.
    Hayakawa I, Teruya T, Kigoshi H (2006) Revised structure of zamamistatin. Tetrahedron Lett 47:155 CrossRefGoogle Scholar
  62. 62.
    Nishiyama S, Yamamura S (1985) Total synthesis of (+/−)-aerothionin, (+/−)-homoaerothionin, and (+)-aerophobin-1. Bull Chem Soc Jpn 58:3453 CrossRefGoogle Scholar
  63. 63.
    Uemura D (1991) Antitumor polyethers. In: Scheuer PJ (ed) Bioorganic Marine Chemistry. Springer, Berlin Heidelberg New York, p 1 Google Scholar
  64. 64.
    Cha JK, Christ WJ, Finan JM, Fujioka H, Kishi Y, Klein LL, Ko SS, Leder J, McWhorter WW Jr, Pfaff KP, Yonaga M, Uemura D, Hirata Y (1982) Stereochemistry of palytoxin 4. Complete structure. J Am Chem Soc 104:7369 CrossRefGoogle Scholar
  65. 65.
    Nakamura H, Asari T, Murai A, Kan Y, Kondo T, Yoshida K, Ohizumi Y (1995) Zooxanthellatoxin-A, a potent vasoconstrictive 62-membered lactone from a symbiotic dinoflagellate. J Am Chem Soc 117:550 CrossRefGoogle Scholar
  66. 66.
    Satake M, Ofuji K, Naoki H, James KJ, Furey A, McMahon T, Silke J, Yasumoto T (1998) Azaspiracid, a new marine toxin having unique spiro ring assemblies, isolated from Irish mussels, Mytilus edulis. J Am Chem Soc 120:9967 CrossRefGoogle Scholar
  67. 67.
    Nicolaou KC, Koftis TV, Vyskocil S, Petrovic G, Ling T, Yamada YM, Tang W, Frederick MO (2004) Structural revision and total synthesis of azaspiracid-1, part 2: Definition of the ABCD domain and total synthesis. Angew Chem Int Ed 43:4318 CrossRefGoogle Scholar
  68. 68.
    Onodera K, Nakamura H, Oba Y, Ojika M (2003) Zooxanthellamide A, a novel polyhydroxy metabolite from a marine dinoflagellate of Symbiodinium sp. Tetrahedron 59:1067 CrossRefGoogle Scholar
  69. 69.
    Onodera K, Nakamura H, Oba Y, Ojika M (2004) Zooxanthellamide B, a novel large polyhydroxy metabolite from a marine dinoflagellate of Symbiodinium sp. Biosci Biotechnol Biochem 68:955 CrossRefGoogle Scholar
  70. 70.
    Onodera K, Nakamura H, Oba Y, Ohizumi Y, Ojika M (2005) Zooxanthellamide Cs: vasoconstrictive polyhydroxylated macrolides with the largest lactone ring size from a marine dinoflagellate of Symbiodinium sp. J Am Chem Soc 127:10406 CrossRefGoogle Scholar
  71. 71.
    Kita M, Kondo M, Koyama T, Yamada K, Matsumoto T, Lee KH, Woo JT, Uemura D (2004) Symbioimine exhibiting inhibitory effect of osteoclast differentiation, from the symbiotic marine dinoflagellate Symbiodinium sp. J Am Chem Soc 126:4794 CrossRefGoogle Scholar
  72. 72.
    Kita M, Ohishi N, Washida K, Kondo M, Koyama T, Yamada K, Uemura D (2005) Symbioimine and neosymbioimine, amphoteric iminium metabolites from the symbiotic dinoflagellate Symbiodinium sp. Bioorg Med Chem 13:5253 CrossRefGoogle Scholar
  73. 73.
    Kita M, Uemura D (2005) Iminium alkaloids from marine invertebrates: structure, biological activity, and biogenesis. Chem Lett 34:454 CrossRefGoogle Scholar
  74. 74.
    Kita M, Sakai E, Uemura D (2006) Pursuit of novel bioactive marine metabolites. J Synth Org Chem Jpn 64:471 Google Scholar
  75. 75.
    Soda H, Shim N, Nakagawa N, Yamaguchi K, Kiosk M, Mochizuki S, Tomoyasu A, Yano K, Got M, Murakami A, Stud E, Morinaga T, Hibachi K, Fukazawa N, Takahashi N, Soda T (1998) Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci USA 95:3597 CrossRefGoogle Scholar
  76. 76.
    Warner TD, Giuliano F, Vojnovic I, Nukasa A, Mitchell JA, Vane JR (1999) Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis. Proc Natl Acad Sci USA 96:7563 CrossRefGoogle Scholar
  77. 77.
    Reddy BS, Hirose Y, Lubet R, Steele V, Kelloff G, Paulson S, Seibert K, Rao CV (2000) Chemoprevention of colon cancer by specific cyclooxygenase-2 inhibitor, celecoxib, administered during different stages of carcinogenesis. Cancer Res 60:293 Google Scholar

Authors and Affiliations

  1. 1.Research Center for Materials ScienceNagoya UniversityNagoyaJapan
  2. 2.Department of ChemistryGraduate School of Science and Institute for Advanced Research, Nagoya UniversityNagoyaJapan

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