Abstract
(–)-Galiellalactone is a secondary fungal metabolite. It was found from dead wood in Chile and first isolated from ascomycetes Galiella rufa (strain A75-86) and A111-95. It has unique architecture. This molecule consists of [5,5,6]-fused tricyclic ring system. The α,β-unsaturated lactone ring present in (–)-galiellalactone acts as Michael acceptor. It has four stereocenters. The tertiary stereocenter has the angular hydroxyl group, which is very important for its bioactivity. This fungal metabolite shows different bioactivities like anti-tumor, anti-inflammatory, anti-HIV, and anti-cancer activities. The unique structural feature along with its excellent bioactivities encouraged us to write this review article. This review comprises the different synthetic approaches with the beauty and uniqueness of various reactions like intramolecular Diels–Alder reaction and Metathesis. Herein, we have discussed the syntheses for the molecule (–)-galiellalactone and its stereoisomers available to date.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Avery MA, Chong WKM, White CJ (1992) Stereoselective Total synthesis of (+)-artemisinin, the antimalarial constituent of Artemisia annua L. J Am Chem Soc 114:974–979. https://doi.org/10.1021/ja00029a028
Baran PS (2018) Natural product total synthesis: as exciting as ever and here to stay. J Am Chem Soc 140:4751–4755. https://doi.org/10.1021/jacs.8b02266
Bollmann F, Jäckel S, Schmidtke L, Schrick K, Reinhardt C, Jurk K, Wu Z, Xia N, Li H, Erkel G, Walter U, Kleinert H, Pautz A (2015) Anti-inflammatory and anti-thrombotic effects of the fungal metabolite galiellalactone in apolipoprotein E-deficient mice. PLoS ONE 10(6):e0130401. https://doi.org/10.1371/journal.pone.0130401
Busker S, Page B, Arnér ES (2020) To inhibit TrxR1 is to inactivate STAT3–Inhibition of TrxR1 enzymatic function by STAT3 small molecule inhibitors. Redox Biol 36:101646. https://doi.org/10.1016/j.redox.2020.101646
Canesin G, Evans-Axelsson S, Hellsten R, Sterner O, Krzyzanowska A, Andersson T, Bjartell A (2016) The STAT3 inhibitor galiellalactone effectively reduces tumor growth and metastatic spread in an orthotopic xenograft mouse model of prostate cancer. Eur Urol 69(3):400–404. https://doi.org/10.1016/j.eururo.2015.06.016
Canesin G, Maggio V, Palominos M, Stiehm A, Contreras HR, Castellón EA, Morote J, Paciucci R, Maitland NJ, Bjartell A, Hellsten R (2020) STAT3 inhibition with galiellalactone effectively targets the prostate cancer stem-like cell population. Sci Rep 10(1):1–12. https://doi.org/10.1038/s41598-020-70948-5
Datta R, Ghosh S (2020) Sequential ring-closing enyne metathesis and intramolecular Diels-Alder reaction: an approach to the synthesis of the core structure of galiellalactone. J Chem Sci 132(1):1–6. https://doi.org/10.1007/s12039-020-01842-w
Escobar Z, Williams H, Phipps R, Karunakaran D, Steele J, Sterner O (2015) New pregaliellalactonoids from Galiella rufa. Phytochem Lett 12:138–141. https://doi.org/10.1016/j.phytol.2015.03.009
Escobar Z, Bjartell A, Canesin G, Evans-Axelsson S, Sterner O, Hellsten R, Johansson MH (2016a) Preclinical characterization of 3β-(N-acetyl l-cysteine methyl ester)-2aβ, 3-dihydrogaliellalactone (GPA512), a prodrug of a direct STAT3 inhibitor for the treatment of prostate cancer. J Med Chem 59(10):4551–4562. https://doi.org/10.1021/acs.jmedchem.5b01814
Escobar Z, Gidlöf R, Johansson M, Hellsten R, Sterner O (2016b) N-Conjugate prodrugs of galiellalactone. Tetrahedron Lett 57(36):4090–4093. https://doi.org/10.1016/j.tetlet.2016.07.094
Escobar Z, Nilsson J, Gidlöf R, Johansson M, Sterner O (2020) Stereoretentive nucleophilic substitution at the tetrasubstituted carbon of galiellalactone. J Org Chem 85(12):7704–7710. https://doi.org/10.1021/acs.joc.0c00152
Furuseth ER, Larsson R, Blanco N, Johansson M, Sterner O (2014) An efficient synthesis of pregaliellalactone and desoxygaliellalactone. Tetrahedron Lett 55(27):3667–3669. https://doi.org/10.1016/j.tetlet.2014.04.117
García V, Lara-Chica M, Cantarero I, Sterner O, Calzado MA, Muñoz E (2016) Galiellalactone induces cell cycle arrest and apoptosis through the ATM/ATR pathway in prostate cancer cells. Oncotarget 7(4):4490–4506. https://doi.org/10.18632/oncotarget.6606
Garrido-Rodríguez M, Ortea I, Calzado MA, Muñoz E, García V (2019) SWATH proteomic profiling of prostate cancer cells identifies NUSAP1 as a potential molecular target for Galiellalactone. J Proteomics 193:217–229. https://doi.org/10.1016/j.jprot.2018.10.012
Gidlöf R, Johansson M, Sterner O (2010) Tandem Pd-catalyzed carbonylation and intramolecular Vinyl Allene Diels−Alder reaction toward galiellalactone analogues. Org Lett 12(22):5100–5103. https://doi.org/10.1021/ol101989m
Hausding M, Tepe M, Übel C, Lehr HA, Röhrig B, Höhn Y, Pautz A, Eigenbrod T, Anke T, Kleinert H, Erkel G, Finotto S (2011) Induction of tolerogenic lung CD4+ T cells by local treatment with a pSTAT-3 and pSTAT-5 inhibitor ameliorated experimental allergic asthma. Int Immunol 23(1):1–15. https://doi.org/10.1093/intimm/dxq451
Hautzel R, Anke H (1990) Screening of basidiomycetes and ascomycetes for plant growth regulating substances. Introduction of the gibberellic acid induced de-novo synthesis of hydrolytic enzymes in embryoless seeds of Triticum aestivum as test system. Naturforsch 45(11–12):1093–1098. https://doi.org/10.18632/oncotarget.6606
Hellsten R, Johansson M, Dahlman A, Dizeyi N, Sterner O, Bjartell A (2008) Galiellalactone is a novel therapeutic candidate against hormone-refractory prostate cancer expressing activated Stat3. Prostate 68(3):269–280. https://doi.org/10.1002/pros.20699
Hellsten R, Johansson M, Dahlman A, Sterner O, Bjartell A (2011) Galiellalactone inhibits stem cell-like ALDH-positive prostate cancer cells. PLoS ONE 6(7):e22118. https://doi.org/10.1371/journal.pone.0022118
Hossain MF, Yadav RN, Mondal S, Jana A, Ghosh S (2013) Intramolecular Diels–Alder route to angularly oxygenated hydrindanes. Synthesis of the functionalized bicylic skeleton present in galiellalactone. Tetrahedron 69(37):7956–7963. https://doi.org/10.1016/j.tet.2013.07.014
Johansson M, Sterner O (2001) Synthesis of (+)-galiellalactone. Absolute configuration of galiellalactone. Org Lett 3(18):2843–2845. https://doi.org/10.1021/ol016286+
Johansson M, Sterner O (2002) Synthesis of (–)-galiellalactone. J Antibiot 55(7):663–665. https://doi.org/10.7164/antibiotics.55.663
Johansson M, Köpcke B, Anke H, Sterner O (2002a) Synthesis of (−)-pregaliellalactone, conversion of (−)-pregaliellalactone to (−)-galiellalactone by mycelia of Galiellarufa. Tetrahedron 58(13):2523–2528. https://doi.org/10.1016/S0040-4020(02)00134-5
Johansson M, Koepcke B, Anke H, Sterner O (2002b) Biologically active secondary metabolites from the ascomycete A111–95 2. Structure elucidation. J Antibiot 55(1):104–106. https://doi.org/10.7164/antibiotics.55.104
Johansson M, Köpcke B, Anke H, Sterner O (2002c) Cyclization of (−)-pregaliellalactone in the fungus galiella rufa. Angew Chem Int Ed 41(12):2158–2160. https://doi.org/10.1002/1521-3773(20020617)41:12%3c2158::AID-ANIE2158%3e3.0.CO;2-P
Johansson M (2002) Biosynthetic and synthetic studies of the fungal metabolite gliellalactone. Ph.D. Dissertation, Lund University, Lund
Kim T, Han YT, An H, Kim K, Lee J, Suh YG (2015) Diastereoselective total synthesis of (−)-galiellalactone. J Org Chem 80(24):12193–12200. https://doi.org/10.1021/acs.joc.5b02121
Ko H, Lee JH, Kim HS, Kim T, Han YT, Suh YG, Chun J, Kim YS, Ahn KS (2019) Novel galiellalactone analogues can target STAT3 phosphorylation and Cause apoptosis in triple-negative breast cancer. Biomolecules 9(5):170. https://doi.org/10.3390/biom9050170
Koepcke B, Johansson M, Sterner O, Anke H (2002) Biologically active secondary metabolites from the ascomycete A111–95 1. Production, isolation and biological activities. J Antibiot 55(1):36–40. https://doi.org/10.7164/antibiotics.55.36
Lebel H, Parmentier M (2007) Copper-catalyzed methylenation reaction: total synthesis of (+)-desoxygaliellalactone. Org Lett 9(18):3563–3566. https://doi.org/10.1021/ol071391q
Lu Y, Zhao S, Zhou S, Chen SC, Luo T (2019) Enantioselective syntheses and application of 4-epi-galiellalactone and the corresponding activity-based probe: from strained bicycles to strained tricycles. Org Biomol Chem 17(7):1886–1892. https://doi.org/10.1039/C8OB01915K
Mutti S, Daubie C, Decalogne F, Fournier R, Rossi P (1996) Enantiospecific synthesis of RPR 107880: a new non peptide substance P antagonist. Tetrahedron Lett 37(18):3125–3128. https://doi.org/10.1016/0040-4039(96)00519-9
Nangia A, Prasuna G (1994) Enantiodivergent syntheses of (R)- and (S)-3,5-dimethylcyclohex-2-en-1-ones from (R)-pulegone. Synth Commun Int J Rapid Commun Synth Org Chem 24:1989–1998. https://doi.org/10.1080/00397919408010206
Nicolaou KC, Yue EW (1997) Total synthesis of selected natural products. Pure Appl Chem 69(3):413–418. https://doi.org/10.1351/pac199769030413
Nussbaum FV, Hanke R, Fahrig T, Benet-Buchholz J (2004) The high-intrinsic diels−alder reactivity of (−)-galiellalactone; generating four quaternary carbon centers under mild conditions. Eur J Org Chem 13:2783–2790. https://doi.org/10.1002/ejoc.200400137
Pérez M, Soler-Torronteras R, Collado JA, Limones CG, Hellsten R, Johansson M, Sterner O, Bjartell A, Calzado MA, Muñoz E (2014) The fungal metabolite galiellalactone interferes with the nuclear import of NF-κB and inhibits HIV-1 replication. Chem Biol Interact 214:69–76. https://doi.org/10.1016/j.cbi.2014.02.012
Rudolph K, Serwe A, Erkel G (2013) Inhibition of TGF-β signaling by the fungal lactones (S)-curvularin, dehydrocurvularin, oxacyclododecindione and galiellalactone. Cytokine 61(1):285–296. https://doi.org/10.1016/j.cyto.2012.10.011
Weidler M, Rether J, Anke T, Erkel G (2000) Inhibition of interleukin-6 signaling by galiellalactone. FEBS Lett 484(1):1–6. https://doi.org/10.1016/S0014-5793(00)02115-3
Zhang Q, Feng Y, Kennedy D (2017) Multidrug-resistant cancer cells and cancer stem cells hijack cellular systems to circumvent systemic therapies, can natural products reverse this? Cell Mol Life Sci 74(5):777–801. https://doi.org/10.1007/s00018-016-2362-3
Acknowledgements
Financial support from University Grants Commission, India [UGC-BSR/Start-Up-Grant/2019-2020 (No. F. 30-515/2020(BSR), FD Diary No. 9718)] is gratefully acknowledged by MFH. SD acknowledges CSIR, New Delhi, India, for Junior Research Fellowship (JRF) (File No. 09/0285(11414)/2021-EMR-I). AD acknowledges “State Fellowship (JRF)” having reference No. 530/R-2022 dated 22/08/2022. The authors also acknowledge the University of North Bengal for providing the basic infrastructural facilities.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Dey, S., Das, A. & Hossain, M.F. Galiellalactone: a review on synthetic strategies and tactics. Chem. Pap. 77, 2329–2342 (2023). https://doi.org/10.1007/s11696-022-02630-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11696-022-02630-1