Skip to main content
SpringerLink
Log in

Variabines A and B: new β-carboline alkaloids from the marine sponge Luffariella variabilis

  • Note
  • Published:
Journal of Natural Medicines Aims and scope Submit manuscript

Abstract

Two new β-carboline alkaloids, variabines A (1) and B (2), were isolated from the Indonesian marine sponge Luffariella variabilis. Their structures were elucidated from spectral data, and 1 was found to be a sulfonated derivative of 2. Although numerous β-carboline alkaloids have been isolated from natural sources to date, 1 is the first β-carboline derivative containing a sulfate group. Compound 2 inhibited chymotrypsin-like activity of the proteasome and Ubc13 (E2)–Uev1A interaction with IC50 values of 4 and 5 μg/mL, respectively, whereas 1 had little effect on the activity or interaction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  1. Adams J (2003) Potential for proteasome inhibition in the treatment of cancer. Drug Discov Today 8:307–315

    Article  PubMed  CAS  Google Scholar 

  2. Thompson JL (2013) Carfilzomib: a second-generation proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma. Ann Pharmacother 47:56–62

    Article  PubMed  Google Scholar 

  3. Glickman MH, Ciechanover A (2002) The ubiquitin–proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 82:373–428

    PubMed  CAS  Google Scholar 

  4. Finley D (2009) Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu Rev Biochem 78:477–513

    Article  PubMed  CAS  Google Scholar 

  5. Bedford L, Lowe J, Dick LR, Mayer RJ, Brownell JE (2011) Ubiquitin-like protein conjugation and the ubiquitin–proteasome system as drug targets. Nat Rev Drug Discov 10:29–46

    Article  PubMed  CAS  Google Scholar 

  6. Cohen P, Tcherpakov M (2010) Will the ubiquitin system furnish as many drug targets as protein kinases? Cell 143:686–693

    Article  PubMed  CAS  Google Scholar 

  7. Tsukamoto S, Yokosawa H (2010) Inhibition of the ubiquitin-proteasome system by natural products for cancer therapy. Planta Med 76:1064–1074

    Article  PubMed  CAS  Google Scholar 

  8. Tsukamoto S, Hirota H, Imachi M, Fujimuro M, Onuki H, Ohta T, Yokosawa H (2005) Himeic acid A: a new ubiquitin-activating enzyme inhibitor isolated from a marine-derived fungus, Aspergillus sp. Bioorg Med Chem Lett 15:191–194

    Article  PubMed  CAS  Google Scholar 

  9. Tsukamoto S, Yamanokuchi R, Yoshitomi M, Sato K, Ikeda T, Rotinsulu H, Mangindaan REP, de Voogd NJ, van Soest RWM, Yokosawa H (2010) Aaptamine, an alkaloid from the sponge Aaptos suberitoides, functions as a proteasome inhibitor. Bioorg Med Chem Lett 20:3341–3343

    Article  PubMed  CAS  Google Scholar 

  10. Yamanokuchi R, Imada K, Miyazaki M, Kato H, Watanabe T, Fujimuro M, Saeki Y, Yoshinaga S, Terasawa H, Iwasaki N, Rotinsulu H, Losung F, Mangindaan REP, Namikoshi M, de Voogd NJ, Yokosawa H, Tsukamoto S (2012) Hirtioreticulines A-E, indole alkaloids inhibiting the ubiquitin-activating enzyme, from the marine sponge Hyrtios reticulatus. Bioorg Med Chem 20:4437–4442

    Article  PubMed  CAS  Google Scholar 

  11. Ushiyama S, Umaoka H, Kato H, Suwa Y, Morioka H, Rotinsulu H, Losung F, Mangindaan REP, de Voogd NJ, Yokosawa H, Tsukamoto S (2012) Manadosterols A and B, sulfonated sterol dimers inhibiting Ubc13-Uev1A interaction, isolated from the marine sponge Lissodendryx fibrosa. J Nat Prod 75:1495–1499

    Article  PubMed  CAS  Google Scholar 

  12. Nakamura Y, Kato H, Nishikawa T, Iwasaki N, Suwa Y, Rotinsulu H, Losung F, Maarisit W, Mangindaan REP, Morioka H, Yokosawa H, Tsukamoto S (2013) Siladenoserinols A-L: new sulfonated serinol derivatives from a tunicate as inhibitors of p53-Hdm2 interaction. Org Lett 15:322–325

    Article  PubMed  CAS  Google Scholar 

  13. Laine A, Topisirovic I, Zhai D, Reed JC, Borden KLB, Ronai Z (2006) Regulation of p53 localization and activity by Ubc13. Mol Cell Biol 26:8901–8913

    Article  PubMed  CAS  Google Scholar 

  14. Topisirovic I, Gutierrez GJ, Chen M, Appella E, Borden KLB, Ronai ZA (2009) Control of p53 multimerization by Ubc13 is JNK-regulated. Proc Natl Acad Sci U S A 106:12676–12681

    Article  PubMed  CAS  Google Scholar 

  15. Gulavita NK, Wright AE, McCarthy PJ, Pomponi SA, Kelly-Borges M, Chin M, Sills MA (1993) Isolation and structure elucidation of 34-sulfatobastadin 13, an inhibitor of the endothelin A receptor, from a marine sponge of the genus Ianthella. J Nat Prod 56:1613–1617

    Article  PubMed  CAS  Google Scholar 

  16. Sato A, Morishita T, Shiraki T, Yoshioka S, Horikoshi H, Kuwano H, Hanzawa H, Hata T (1993) Aldose reductase inhibitors from a marine sponge, Dictyodendrilla sp. J Org Chem 58:7632–7634

    Article  CAS  Google Scholar 

  17. Cain M, Weber RW, Guzman F, Cook JM, Barker SA, Rice KC, Crawley JN, Paul SM, Skolnick P (1982) β-Carbolines: synthesis and neurochemical and pharmacologicalactions on brain benzodiazepine receptors. J Med Chem 25:1081–1091

    Article  PubMed  CAS  Google Scholar 

  18. de Silva ED, Scheuer PJ (1980) Manoalide, an antibiotic sesterterpenoid from the marine sponge Luffariella variabilis (polejaeff). Tetrahedron Lett 21:1611–1614

    Article  Google Scholar 

  19. Glaser KB, Jacobs RS (1986) Molecular pharmacology of manoalide. Inactivation of bee venom phospholipase A2. Biochem Pharmacol 35:449–453

    Article  PubMed  CAS  Google Scholar 

  20. Glaser KB, de Carvalho MS, Jacobs RS, Kernan MR, Faulkner DJ (1989) Manoalide: structure-activity studies and definition of the pharmacophore for phospholipase A2 inactivation. Mol Pharmacol 36:782–788

    PubMed  CAS  Google Scholar 

  21. de Silva ED, Scheuer PJ (1981) Three new sesterterpenoid antibiotics from the marine sponge Luffariella variabilis (polejaff). Tetrahedron Lett 22:3147–3150

    Article  Google Scholar 

  22. Kernan MR, Faulkner DJ, Jacobs RS (1987) The luffariellins, novel antiinflammatory sesterterpenes of chemotaxonomic importance from the marine sponge Luffariella variabilis. J Org Chem 52:3081–3083

    Article  CAS  Google Scholar 

  23. Potts BCM, Capon RJ, Faulkner DJ (1992) Luffalactone and (4E,6E)-dehydromanoalide from the sponge Luffariella variabilis. J Org Chem 57:2965–2967

    Article  CAS  Google Scholar 

  24. König GM, Wright AD, Sticher O (1992) Four new antibacterial sesterterpenes from a marine sponge of the genus Luffariella. J Nat Prod 55:174–178

    Article  PubMed  Google Scholar 

  25. Ettinger-Epstein P, Motti CA, de Nys R, Wright AD, Battershill CN, Tapiolas DM (2007) Acetylated sesterterpenes from the Great Barrier Reef sponge Luffariella variabilis. J Nat Prod 70:648–651

    Article  PubMed  CAS  Google Scholar 

  26. Blunt JW, Copp BR, Keyzers RA, Munro MHG, Prinsep MR (2013) Marine natural products. Nat Prod Rep 30:237–323

    Article  PubMed  CAS  Google Scholar 

  27. Tsukamoto S, Takeuchi T, Rotinsulu H, Mangindaan REP, van Soest RWM, Ukai K, Kobayashi H, Namikoshi M, Ohta T, Yokosawa H (2008) Leucettamol A: a new inhibitor of Ubc13-Uev1A interaction isolated from a marine sponge, Leucetta aff. microrhaphis. Bioorg Med Chem Lett 18:6319–6320

    Article  PubMed  CAS  Google Scholar 

  28. Takeuchi T, Yokosawa H (2005) ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating activity. Biochem Biophys Res Commun 336:9–13

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Prof. M. Namikoshi and Dr. K. Ukai of Tohoku Pharmaceutical University and Dr. H. Kobayashi of the University of Tokyo for collection of the sponge. This work was supported by Grants-in-aid for Scientific Research (Nos. 22310138 and 22406001) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and also by grants from the Naito Foundation, the Astellas Foundation for Research on Metabolic Disorders, and the Uehara Memorial Foundation.

Author information

Authors and Affiliations

  1. Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, 862-0973, Japan

    Eriko Sakai, Hikaru Kato & Sachiko Tsukamoto

  2. Faculty of Agriculture, Universitas Pembangunan Indonesia, Manado, 95361, Indonesia

    Henki Rotinsulu

  3. Faculty of Fisheries and Marine Science, Sam Ratulangi University, Kampus Bahu, Manado, 95115, Indonesia

    Fitje Losung & Remy E. P. Mangindaan

  4. Netherlands Centre for Biodiversity Naturalis, P.O. Box 9517, 2300 RA, Leiden, The Netherlands

    Nicole J. de Voogd

  5. School of Pharmacy, Aichi Gakuin University, Chikusa-ku, Nagoya, 464-8650, Japan

    Hideyoshi Yokosawa

Authors
  1. Eriko Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hikaru Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Henki Rotinsulu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fitje Losung
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Remy E. P. Mangindaan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nicole J. de Voogd
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hideyoshi Yokosawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Sachiko Tsukamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sachiko Tsukamoto.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sakai, E., Kato, H., Rotinsulu, H. et al. Variabines A and B: new β-carboline alkaloids from the marine sponge Luffariella variabilis . J Nat Med 68, 215–219 (2014). https://doi.org/10.1007/s11418-013-0778-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11418-013-0778-8

Keywords

Search

Navigation