Antiviral Agents from Novel Marine and Terrestrial Sources

  • Kenneth L. Rinehart
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 312)


Pharmaceutical products are derived from only two sources--natural products and organic synthesis; indeed, natural products have proven a cornucopia of drugs through the years. Systematic searches for antiviral agents in nature, however, are both rare and recent. Our own extensive efforts to identify natural products with antiviral activity began with a one-month expedition to the Western Caribbean in 1978 on board the National Science Foundation’s R/V Alpha Helix (Alpha Helix Caribbean Expedition, AHCE 1978).1 The expedition started in Panama, extended to Cozumel, Mexico, and visited roughly 20 collecting sites en route. The focus was on Belize, the site of the largest reef in the Western Hemisphere. During the expedition we collected somewhat over 500 different species and a total of about 1000 samples. The scientific crew of this expedition included Dr. Robert G. Hughes, Jr., Roswell Park Memorial Institute, Buffalo, NY, who carried out antiviral assays on shipboard by using a standard Herpes simplex virus, type 1 (HSV-1), assay, with the virus being grown in monkey kidney, CV-1, cells.2 This allowed us to identify not only antiviral, but also cytotoxic species. Because we had no prior information on active species, our goal was to collect by SCUBA every marine invertebrate and alga we could find and to assay every sample for antiviral activity. Then, while on location, we planned to collect more of the bioactive species.


Antiviral Activity Dengue Virus Antiviral Agent Total Synthesis Rift Valley Fever 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    K. L. Rinehart Jr., P. D. Shaw, L. S. Shield, J. B. Gloer, G. C. Harbour, M. E. S. Koker, D. Samain, R. E. Schwartz, A. A. Tymiak, D. L. Weller, G. T. Carter, M. H. G. Munro, R. G. Hughes Jr., H. E. Renis, E. B. Swynenberg, D. A. Stringfellow, J. J. Vavra, J. H. Coats, G. E. Zurenko, S. L. Kuentzel, L. H. Li, G. J. Bakus, R. C. Brusca, L. L. Craft, D. N. Young, and J. L. Connor, Marine natural products as sources of antiviral, antimicrobial, and antineoplastic agents, Pure Appl. Chem. 53:795–817 (1981).CrossRefGoogle Scholar
  2. 2.
    A. C. Schroeder, R. G. Hughes Jr., and A. Bloch, Synthesis and biological effects of acyclic pyrimidine nucleoside analogues, J. Med. Chem. 24:1078–1083 (1981).CrossRefPubMedGoogle Scholar
  3. 3.
    K. L. Rinehart, Screening to detect biological activity, in “Biomedical Importance of Marine Organisms,” Memoirs of the California Academy of Sciences Number 13, D. G. Fautin, Ed., California Academy of Sciences, San Francisco (1988); pp 13–22.Google Scholar
  4. 4.
    T. G. Holt, The isolation and structural characterization of the ecteinascidins, Ph.D. Dissertation, University of Illinois, Urbana, 1986; Chem. Abstr. 106:193149u (1987); Diss. Abstr. Int. B 47:3771–3772 (1987).Google Scholar
  5. 5.
    K. L. Rinehart and L. S. Shield, Novel bioactive natural products from marine organisms, in “Topics in Pharmaceutical Sciences 1989,” D. D. Breimer, D. J. A. Crommelin, and K. K. Midha, Eds., Amsterdam Medical Press B.V., Noordwijk, Netherlands (1989); pp 613–626.Google Scholar
  6. 6.
    K. L. Rinehart, T. G. Holt, N. L. Fregeau, P. A. Keifer, G. R. Wilson, T. J. Perun Jr., R. Sakai, A. G. Thompson, J. G. Stroh, L. S. Shield, D. S. Seigler, L. H. Li, D. G. Martin, C. J. P. Grimmelikhuijzen, and G. Gade, Bioactive compounds from aquatic and terrestrial sources, J. Nat. Prod. 53:771–792 (1990).CrossRefPubMedGoogle Scholar
  7. 7.
    P. A. Keifer, R. E. Schwartz, M. E. S. Koker, R. G. Hughes Jr., D. Rittschof, and K. L. Rinehart, Bioactive bromopyrrole metabolites from the Caribbean sponge Agelas conifera, J. Org. Chem. 56:000–000 (1991).Google Scholar
  8. 8.
    K. L. Rinehart Jr., Bioactive metabolites from the Caribbean sponge Agelas coniferin, U.S. Patent No. 4,737,510, April 12, 1988; Chem. Abstr. 109:216002u (1988).Google Scholar
  9. 9.
    R. P. Walker, D. J. Faulkner, D. Van Engen, and J. Clardy, Sceptrin, an antimicrobial agent from the sponge Agelas sceptrum,J. Am. Chem. Soc. 103:6772–6773 (1981).CrossRefGoogle Scholar
  10. 10.
    K. L. Rinehart Jr., J. Kobayashi, G. C. Harbour, J. Gilmore, M. Mascal, T. G. Holt, L. S. Shield, and F. Lafargue, Eudistomins A-Q, (3-carbolines from the antiviral Caribbean tunicate Eudistoma olivaceum, J. Am. Chem. Soc. 109:3378–3387 (1987).CrossRefGoogle Scholar
  11. 11.
    K. L. Rinehart Jr., G. C. Harbour, and J. Kobayashi, Antiviral eudistomins from a marine tunicate, U.S. Patent No. 4,631,149, Dec. 23, 1986; Chem. Abstr. 102:226023w (1985).Google Scholar
  12. 12.
    M. Nakagawa, J.-J. Liu, and T. Hino, Total synthesis of (-)-eudistomin L and (-)- debromoeudistomin L, J. Am. Chem. Soc. 111:2721–2722 (1989).CrossRefGoogle Scholar
  13. 13.
    P. H. H. Hermkens, J. H. v. Maarseveen, H. C. J. Ottenheijm, C. G. Kruse, and H. W. Scheeren, Intramolecular Pictet-Spengler reaction of N-Alkoxytryptamines. 3. Stereoselective synthesis of (-)-debromoeudistomin L and (-)-O-methyldebromoeudistomin E and their stereoisomers, J. Org. Chem. 55:3998–4006 (1990).CrossRefGoogle Scholar
  14. 14.
    I. W. J. Still and J. R. Strautmanis, “Synthesis of N(10)-acetyleudistomin L, Tetrahedron Lett. 30:1041–1044 (1989).CrossRefGoogle Scholar
  15. 15.
    M. P. Kirkup, B. B. Shankar, S. McCombie, A. K. Ganguly, and A. T. McPhail, A concise route to the oxathiazepine containing eudistomin skeleton and some carba-analogs, Tetrahedron Lett. 30:6809–6812 (1989).CrossRefGoogle Scholar
  16. 16.
    K. L. Rinehart Jr., J. B. Gloer, J. C. Cook, Jr. S. A. Mizsak, and T. A. Scahill, Structures of the didemnins, antiviral and cytotoxic depsipeptides from a Caribbean tunicate, J. Am. Chem. Soc. 103:1857–1859 (1981).CrossRefGoogle Scholar
  17. 17.
    K. L. Rinehart Jr., Didemnins A, B, C, and derivatives thereof, as antiviral agents, U.S. Patent No. 4,493,796, Jan. 15, 1985; Chem. Abstr. 103:76241v (1985).Google Scholar
  18. 18.
    R. Sakai and K. L. Rinehart, Didemnin X and Y: new cytotoxic cyclic depsipeptides from the tunicate Trididemnum solidum, 197th ACS National Meeting, Dallas, TX, April 9–14, 1989, Abstract ORGN 171.Google Scholar
  19. 19.
    K. L. Rinehart, R. Sakai, and J. G. Stroh, Novel cytotoxic cyclic depsipeptides from the tunicate Trididemnum solidum,U.S. Patent Appl. Ser. No. 335,903, Apr. 10, 1989.Google Scholar
  20. 20.
    K. L. Rinehart, Novel anti-viral and cytotoxic agents, British Patent Appl. #8922026.3, Sep. 29, 1989.Google Scholar
  21. 21.
    K. L. Rinehart, V. Kishore, K. C. Bible, R. Sakai, D. W. Sullins, and K.-M. Li, Didemnins and tunichlorin: novel natural products from the marine tunicate Trididemnum solidum, J. Nat. Prod. 51:1–21 (1988).CrossRefPubMedGoogle Scholar
  22. 22.
    K. L. Rinehart, V. Kishore, S. Nagarajan, R. J. Lake, J. B. Gloer, F. A. Bozich, K.-M. Li, R. E. Maleczka Jr., W. L. Todsen, M. H. G. Munro, D. W. Sullins, and R. Sakai, Total synthesis of didemnins A, B, and C, J. Am. Chem. Soc. 109:6846–6848 (1987).CrossRefGoogle Scholar
  23. 23.
    K. L. Rinehart Jr., J. B. Gloer, R. G. Hughes Jr., H. E. Renis, J. P. McGovren, E. B. Swynenberg, D. A. Stringfellow, S. L. Kuentzel, and L. H. Li, Didemnins: antiviral and antitumor depsipeptides from a Caribbean tunicate, Science 212:933–935 (1981).CrossRefPubMedGoogle Scholar
  24. 24.
    K. L. Rinehart Jr., J. B. Gloer, G. R. Wilson, R. G. Hughes Jr., L. H. Li, H. E. Renis, and J. P. McGovren, Antiviral and antitumor compounds from tunicates, Fed. Proc. 42:87–90 (1983)PubMedGoogle Scholar
  25. 25.
    K. L. Rinehart Jr., J. C. Cook Jr., R. C. Pandey, L. A. Gaudioso, H. Meng, M. L. Moore, J. B. Gloer, G. R. Wilson, R. E. Gutowsky, P. D. Zierath, L. S. Shield, L. H. Li, H. E. Renis, J. P. McGovren, and P. G. Canonico, Biologically active peptides and their mass spectra, Pure Appl. Chem. 54:2409–2424 (1982).CrossRefGoogle Scholar
  26. 26.
    K. L. Rinehart, Didemnin and its biological properties, in “Peptides. Chemistry and Biology,” G. R. Marshall, Ed., ESCOM, Leiden, The Netherlands (1988); pp 626–631.Google Scholar
  27. 27.
    H. G. Chun, B. Davies, D. Hoth, M. Suffness, J. Plowman, K. Flora, C. Grieshaber, and B. Leyland-Jones, Didemnin B: the first marine compound entering clinical trials as an antineoplastic agent, Invest. New Drugs 4:279–284 (1986).CrossRefPubMedGoogle Scholar
  28. 28.
    D. W. Montgomery, A. Celniker, and C. F. Zukoski, Didemnin B-an immunosuppressive cyclic peptide that stimulates murine hemagglutinating antibody responses and induces leukocytosis in vivo, Transplantation 43:133–139 (1987).CrossRefPubMedGoogle Scholar
  29. 29.
    D. H. Russell, A. R. Buckley, D. W. Montgomery, N. A. Larson, P. W. Gout, C. T. Beer, C. W. Putnam, C. F. Zukoski, and R. Kibler, Prolactin-dependent mitogenesis in Nb 2 node lymphoma cells: effects of immunosuppressive cyclopeptides, J. Immunol. 138:276–284 (1987).PubMedGoogle Scholar
  30. 30.
    E. Maldonado, J. A. Lavergne, and E. Kraiselburd, Didemnin A inhibits the in vitro replication of dengue virus types 1, 2 and 3, Puerto Rico Health Sci. J. 1:22–25 (1982).Google Scholar
  31. 31.
    H. E. Renis, B. A. Court, E. E. Eidson, E. B. Swynenberg, J. B. Gloer, and K. L. Rinehart Jr., Didemnins--antiviral properties of depsipeptides from a marine tunicate, 21st Intersci. Conf. Antimicrob. Agents Chemother., Chicago, IL, Nov. 4–6, 1981, Abstract #189.Google Scholar
  32. 32.
    P. G. Canonico, W. L. Pannier, J. W. Huggins, and K. L. Rienehart, Inhibition of RNA viruses in vitro and in Rift Valley fever-infected mice by didemnins A and B, Antimicrob. Agents Chemother. 22:696–697 (1982).CrossRefPubMedGoogle Scholar
  33. 33.
    S. D. Weed and D. A. Stringfellow, Didemnins A and B. Effectiveness against cutaneous herpes simplex virus in mice, Antiviral Res. 3:269–274 (1983).CrossRefPubMedGoogle Scholar
  34. 34.
    N. B. Perry, J. W. Blunt, M. H. G. Munro, and A. M. Thompson, Antiviral and antitumor agents from a New Zealand sponge, Mycale sp. 2. Structures and solution conformations of mycalamides A and B, J. Org. Chem. 55:223–227 (1990).CrossRefGoogle Scholar
  35. 35.
    S. Sakemi, T. Ichiba, S. Kohmoto, G. Saucy, and T. Higa, Isolation and structure elucidation of onnamide A, a new bioactive metabolite of a marine sponge, Theonella sp., J. Am. Chem. Soc. 110:4851–4853 (1988).CrossRefGoogle Scholar
  36. 36.
    C. Cardani, D. Ghiringhelli, R. Mondelli, and A. Quilico, The structure of pederin, Tetrahedron Lett. 1965:2537–2545 (1965).CrossRefGoogle Scholar
  37. 37.
    J. W. Blunt, M. P. Hartshorn, T. J. McLennan, M. H. G. Munto, W. T. Robinson, and S. C. Yorke, Thyrsiferol: a squalene-derived metabolite of Laurencia thyrsifera,Tetrahedron Lett. 1978:69–72 (1978).CrossRefGoogle Scholar
  38. 38.
    Y. Kato, N. Fusetani, S. Matsunaga, K. Hashimoto, R. Sakai, T. Higa, and Y. Kashman, Antitumor macrodiolides isolated from a marine sponge Theonella sp.: structure revision of misakinolide A, Tetrahedron Lett. 28:6225–6228 (1987).CrossRefGoogle Scholar
  39. 39.
    S. Kohmoto, O. J. McConnell, A. Wright, and S. Cross, Isospongiadiol, a cytotoxic and antiviral diterpene from a Caribbean deep water marine sponge, Spongia sp., Chem. Lett. 1687–1690 (1987).Google Scholar
  40. 40.
    G. R. Wilson and K. L. Rinehart, Antiviral compositions derived from fireflies and their methods of use, U.S. Patent No. 4,847, 246, Jul. 11, 1989; Chem. Abstr. 112:48775q (1990).Google Scholar
  41. 41.
    J. Meinwald, D. F. Wiemer, and T. Eisner, Lucibufagins. 2. Esters of 12-oxo-2β,5β,11α-trihydroxybufalin, the major defensive steroids of the firefly Photinus pyralis (Coleoptera: Lampyridae), J. Am. Chem. Soc. 101:3055–3060 (1979).CrossRefGoogle Scholar
  42. 42.
    G. R. Pettit, J. E. Leet, C. L. Herald, Y. Kamano, F. E. Boettner, L. Baczynskyj, and R. A. Neiman, Isolation and structure of bryostatins 12 and 13, J. Org. Chem. 52:2854–2860 (1987).CrossRefGoogle Scholar
  43. 43.
    R. S. Jacobs, P. Culver, R. Langdon, T. O’Brien, and S. White, Some pharmacological observations on marine natural products, Tetrahedron 41:981–984 (1985).CrossRefGoogle Scholar
  44. 44.
    A. J. Weinheimer and R. L. Spraggins, “The occurrence of two new prostaglandin derivatives (15-epi-PGA2 and its acetate, methyl ester) in the gorgonian Plexaura homomalla. Chemistry of coelenterates. XV., Tetrahedron Lett. 1969:5185–5188 (1969).CrossRefGoogle Scholar
  45. 45.
    F. Lafargue and G. Duclaux, Premier exemple, en Atlantique tropical, d’une association symbiotique entre une ascidie didemnidae et une cyanophycde chroococcale: Trididemnum cyanophorum nov. sp. et Synechocystis trididemni nov. sp., Ann. Inst. oceanogr. 55:163–184 (1979).Google Scholar
  46. 46.
    J. Sybesma, F. C. van Duyl, and R. P. M. Bak, The ecology of the tropical compound ascidian Trididemnum solidum. III. Symbiotic association with unicellular algae, Mar. Ecol. Prog. Ser. 6:53–59 (1981).CrossRefGoogle Scholar
  47. 47.
    T. Hino, Z. Lai, H. Seki, R. Hara, T. Kuramochi, and M. Nakagawa, Synthesis of eudistomins H, I, and P, 0-carboline derivatives from Eudistoma olivaceurn with antiviral and antimicrobial activity, Chem. Pharm. Bull. 37:2596–2600 (1989).CrossRefGoogle Scholar
  48. 48.
    B. C. VanWagenen and J. H. Cardellina II, Short, efficient syntheses of the antibiotics eudistomins I and T, Tetrahedron Len. 30:3605–3608 (1989).CrossRefGoogle Scholar
  49. 49.
    H. H. Wasserman and T. A. Kelly, The chemistry of vicinal tricarbonyl compounds. Short syntheses of eudistomins T, I, and M, Tetrahedron Lea. 30:7117–7120 (1989).CrossRefGoogle Scholar
  50. 50.
    Y. Hamada, Y. Kondo, M. Shibata, and T. Shioiri, Efficient total synthesis of didemnins A and B, J. Am. Chem. Soc. 111:669–673 (1989).CrossRefGoogle Scholar
  51. 51.
    U. Schmidt, M. Kroner, and H. Griesser, Total synthesis of the didemnins - 2. Synthesis of didemnin A, B, C and Prolyldidemnin A, Tetrahedron Lett. 29:4407–4408 (1988).CrossRefGoogle Scholar
  52. 52.
    W.-R. Li, W. R. Ewing, B. D. Harris, and M. M. Joullie, Total synthesis and structural investigations of didemnins A, B, and C, J. Am. Chem. Soc. 112:7659–7672 (1990).CrossRefGoogle Scholar
  53. 53.
    P. Jouin, J. Poncet, M.-N. Dufour, A. Pantaloni, and B. Castro, Synthesis of the cyclodepsipeptide nordidemnin B, a cytotoxic minor product isolated from the sea tunicate Trididemnum cyanophorum, J. Org. Chem. 54:617–627 (1989).CrossRefGoogle Scholar
  54. 54.
    C. Y. Hong and Y. Kishi, Total synthesis of mycalamides A and B, J. Org. Chem. 55:4242–4245 (1990).CrossRefGoogle Scholar
  55. 55.
    W. Bergmann and R. J. Feeney, Contributions to the study of marine products. XXXII. The nucleosides of sponges. I. J. Org. Chem. 16:981–987 (1951).CrossRefGoogle Scholar
  56. 56.
    J. S. Evans, E. A. Musser, G. D. Mengel, K. R. Forsblad, and J. H. Hunter, Antitumor activity of 1–3-D-arabinofuranosylcytosine hydrochloride, Proc. Soc. Exp. Biol. Med. 106:350–353 (1961).PubMedGoogle Scholar
  57. 57.
    D. Pavan-Langston, R. A. Buchanan, and C. A. Alford Jr., “Adenosine Arabinoside: An Antiviral Agent,” Raven Press, New York (1975).Google Scholar

Copyright information

© Springer Science+Business Media New York 1992

Authors and Affiliations

  • Kenneth L. Rinehart
    • 1
  1. 1.Department of ChemistryUniversity of IllinoisUrbanaUSA

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