Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Thielavins: tuned biosynthesis and LR-HSQMBC for structure elucidation

Abstract

A series of thielavins I, V, and Q (13) and the previously undescribed thielavin Z8 (4) were isolated from cultures of a fungal Shiraia-like sp. (strain MSX60519) that were grown under a suite of media and light conditions, with enhanced biosynthesis noted using rice as a substrate with 12:12 h light:dark cycles. Conversely, oatmeal medium and continuous white light-emitting diode light exposure negatively affected the production of these compounds, at least by strain MSX60519. The structure of 4 was determined using NMR spectroscopic data and mass fragmentation patterns. Of note, the utility of LR-HSQMBC and NOESY NMR experiments in the structural elucidation of these hydrogen-deficient natural products was demonstrated. Compounds 14 exhibited cytotoxic activity at the micromolar level against human breast, ovarian, and melanoma cancer cell lines.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Data availability

1H NMR, 13C NMR and (+)-HRESIMS data for compounds 14. 2D NMR data (HSQC and HMBC) for the new compound (4). MS fragmentation patterns of 14. LR-HSQMBC NMR for 1 & 4 and NOESY NMR for 3 & 4. The 1D and 2D NMR spectra for 14 were deposited in Harvard Dataverse and can be freely accessed through https://doi.org/10.7910/DVN/QF3WOJ.

References

  1. 1.

    Al Subeh ZY, et al. Enhanced production and anticancer roperties of photoactivated perylenequinones. J Nat Prod. 2020;83:2490–500.

    CAS  Article  Google Scholar 

  2. 2.

    Al Subeh ZY, et al. Correction to enhanced production and anticancer properties of photoactivated perylenequinones. J Nat Prod. 2020; https://doi.org/10.1021/acs.jnatprod.0c01289.

  3. 3.

    de Medeiros LS, Murgu M, deSouza AQL, Rodrigues-Fo E. Antimicrobial depsides produced by Cladosporium uredinicola, an endophytic fungus isolated from Psidium guajava fruits. Helv Chim Acta. 2011;94:1077–84.

    Article  Google Scholar 

  4. 4.

    Take Y, Inouye Y, Nakamura S, Allaudeen HS, Kubo A. Comparative studies of the inhibitory properties of antibiotics on human immunodeficiency virus and avian myeloblastosis virus reverse transcriptases and cellular DNA polymerases. J Antibiot. 1989;42:107–15.

    CAS  Article  Google Scholar 

  5. 5.

    Sakemi S, et al. Thielavins as glucose-6-phosphatase (G6Pase) inhibitors: producing strain, fermentation, isolation, structural elucidation and biological activities. J Antibiot. 2002;55:941–51.

    CAS  Article  Google Scholar 

  6. 6.

    Rivera-Chávez J, González-Andrade M, del Carmen González M, Glenn AE, Mata R. Thielavins A, J and K: α-glucosidase inhibitors from MEXU 27095, an endophytic fungus from Hintonia latiflora. Planta Med. 2013;79:198–205.

    Article  Google Scholar 

  7. 7.

    Han Z, et al. Thielavins W-Z7, new antifouling thielavins from the marine-derived fungus Thielavia sp. UST030930-004. Mar Drugs. 2017;15:128.

    Article  Google Scholar 

  8. 8.

    Ayers S, et al. Thielavin B methyl ester: a cytotoxic benzoate trimer from an unidentified fungus (MSX 55526) from the Order Sordariales. Tetrahedron Lett. 2011;52:5733–5.

    CAS  Article  Google Scholar 

  9. 9.

    Kinghorn AD, et al. Discovery of anticancer agents of diverse natural origin. Anticancer Res. 2016;36:5623–37.

    CAS  Article  Google Scholar 

  10. 10.

    Togashi K, Ko HR, Ahn JS, Osada H. Inhibition of telomerase activity by fungus metabolites, CRM646-A and thielavin B. Biosci Biotechnol Biochem. 2001;65:651–3.

    CAS  Article  Google Scholar 

  11. 11.

    Rojas IS, Lotina-Hennsen B, Mata R. Effect of lichen metabolites on thylakoid electron transport and photophosphorylation in isolated spinach chloroplasts. J Nat Prod. 2000;63:1396–9.

    CAS  Article  Google Scholar 

  12. 12.

    Kitahara N, Endo A, Furuya K, Takahashi S. Thielavin A and B, new inhibitors of prostaglandin biosynthesis produced by Thielavia terricola. J Antibiot. 1981;34:1562–8.

    CAS  Article  Google Scholar 

  13. 13.

    Kitahara N, Haruyama H, Hata T, Takahashi S. The structures of thielavins A, B and C. Prostaglandin synthetase inhibitors from fungi. J Antibiot. 1983;36:599–600.

    CAS  Article  Google Scholar 

  14. 14.

    Jang J-P, et al. Inhibition of indoleamine 2,3-dioxygenase by thielavin derivatives from a soil fungus, Coniochaeta sp. 10F058. J Antibiot. 2014;67:331–3.

    CAS  Article  Google Scholar 

  15. 15.

    Matsumoto K, et al. Isolation and biological activity of thielocins: novel phospholipase A2 inhibitors produced by Thielavia terricola RF-143. J Antibiot. 1995;48:106–12.

    CAS  Article  Google Scholar 

  16. 16.

    de Medeiros LS, Murgu M, de-Souza AQ, Rodrigues-Fo E. Erratum: antimicrobial depsides produced by Cladosporium uredinicola, an endophytic fungus isolated from Psidium guajava fruits. Helv Chim Acta. 2013;96:1406–7.

    Article  Google Scholar 

  17. 17.

    de Medeiros LS, et al. Dereplication-guided isolation of depsides thielavins S-T and lecanorins D-F from the endophytic fungus Setophoma sp. Phytochemistry .2015;111:154–62.

    Article  Google Scholar 

  18. 18.

    Elyashberg M. Identification and structure elucidation by NMR spectroscopy. Trends Anal Chem. 2015;69:88–97.

    CAS  Article  Google Scholar 

  19. 19.

    Keifer PA. NMR spectroscopy in drug discovery: tools for combinatorial chemistry, natural products, and metabolism research. Prog Drug Res. 2000;55:137.

    CAS  Article  Google Scholar 

  20. 20.

    Du L, King JB, Cichewicz RH. Chlorinated polyketide obtained from a Daldinia sp. treated with the epigenetic modifier suberoylanilide hydroxamic acid. J Nat Prod. 2014;77:2454–8.

    CAS  Article  Google Scholar 

  21. 21.

    Bills GF, Gloer JB. Biologically active secondary metabolites from the fungi. Microbiol Spectr. 2016;4. FUNK-0009-2016. https://www.asmscience.org/content/journal/microbiolspec/10.1128/microbiolspec.FUNK-0009-2016.

  22. 22.

    Williamson RT, Buevich AV, Martin GE, Parella T. LR-HSQMBC: a sensitive NMR technique to probe very long-range heteronuclear coupling pathways. J Org Chem. 2014;79:3887–94.

    CAS  Article  Google Scholar 

  23. 23.

    Tran TD et al. NMR characterization of rearranged staurosporine aglycone analogues from the marine sponge Damiria sp. Magn Reson Chem. 2019; https://doi.org/10.1002/mrc.4932.

  24. 24.

    Chan STS, et al. Characterization and synthesis of Eudistidine C, a bioactive marine alkaloid with an intriguing molecular scaffold. J Org Chem. 2016;81:10631–40.

    CAS  Article  Google Scholar 

  25. 25.

    Motiram-Corral K, Nolis P, Parella T, Sauri J. LR-HSQMBC versus LR-selHSQMBC: enhancing the observation of tiny long-range heteronuclear NMR correlations. J Nat Prod. 2020;83:1275–82.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Institutes of Health via the National Cancer Institute (P01 CA125066). We thank Dr Tamam El-Elimat, Dr Laura Flores-Bocanegra, and Tyler Graf for helpful suggestions.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Nicholas H. Oberlies.

Ethics declarations

Conflict of interest

NHO declares that he is a member of the Scientific Advisory Board of Mycosynthetix, Inc.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Al Subeh, Z.Y., Raja, H.A., Maldonado, A. et al. Thielavins: tuned biosynthesis and LR-HSQMBC for structure elucidation. J Antibiot 74, 300–306 (2021). https://doi.org/10.1038/s41429-021-00405-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41429-021-00405-6

Further reading

Search

Quick links