Hyperforin is a major polyprenylated acylphloroglucinol from Hypericum perforatum L. whose complex stereochemistry is central to its chemical identity, biological activity, and biosynthetic reproducibility. This review critically reassesses the structural and stereochemical evidence for hyperforin and discusses its biological activity in relation to phytochemical characterization, stability, and analytical methodology. Hyperforin represents a rare example of a natural product whose biological significance can only be understood through the combined interpretation of analytical chemistry, stereochemistry, total synthesis, and pharmacology. The antimicrobial properties of Hypericum perforatum extracts, particularly against antibiotic-resistant cocci, were intensively investigated at the University of Oslo during 1978-1979. Subsequent investigations between 1979 and 1985 focused on the chemical composition of the plant, the isolation of hyperforin, and its structural characterization. These studies led to a revision of earlier structural representations of hyperforin. The first mass spectrometric characterization of hyperforin was followed by X-ray crystallographic analysis of its 3,5-dinitrobenzoate ester, which established the relative stereochemistry. Subsequent crystallographic analysis of the p-bromobenzoate ester demonstrated that earlier stereochemical assignments required correction, although erroneous structural representations continue to be cited in the literature. Accurate stereochemical determination is essential for understanding the biological activity, synthetic reproducibility, and structure-function relationships of hyperforin. Owing to its lipophilicity, chemical instability, membrane interactions, antimicrobial and immunomodulatory activity, and antitumor-related effects, hyperforin merits further investigation as a structurally complex and multifunctional bioactive natural product.
References
[1]
Brondz, I. (2025) To Remembrance Larysa Karaliova. VoiceofthePublisher, 11, 1-3. https://doi.org/10.4236/vp.2025.111001
[2]
Brondz, I., Greibrokk, T. and Aasen, A.J. (1983) N-Alkanes of Hypericum perforatum: A Revision. Phytochemistry, 22, 295-296. https://doi.org/10.1016/s0031-9422(00)80110-7
[3]
Brondz, I., Greibrokk, T. and Aasen, A.J. (1983) N-1-Alkanols of Hypericum perforatum. JournalofNaturalProducts, 46, 940-941. https://doi.org/10.1021/np50030a025
[4]
Zapun, A., Vernet, T. and Pinho, M.G. (2008) The Different Shapes of Cocci. FEMSMicrobiologyReviews, 32, 345-360. https://doi.org/10.1111/j.1574-6976.2007.00098.x
[5]
Brondz, I. (2016) Super Antibiotics, Part I. Hyperforin. VoiceofthePublisher, 2, 19-27. https://doi.org/10.4236/vp.2016.24004
[6]
Brondz, I. (2016) Super Antibiotics, Part II. Hyperforin, Mass Spectroscopy (MS) and Gas Chromatography-Mass Spectrometry (GC-MS), Evidence of Permeability of the Blood-Testis Barrier (BTB) and the Blood-Brain Barrier (BBB) to Hyperforin. InternationalJournalofAnalyticalMassSpectrometryandChromatography, 4, 66-73. https://doi.org/10.4236/ijamsc.2016.44007
[7]
Kaufmann, S.H.E., Dorhoi, A., Hotchkiss, R.S. and Bartenschlager, R. (2018) Host-directed Therapies for Bacterial and Viral Infections. NatureReviewsDrugDiscovery, 17, 35-56. https://doi.org/10.1038/nrd.2017.162
[8]
Gurevich, A.I., Dobrynin, V.N., Kolosov, M.N., Popravko, S.A., Ryabova, I.D., Chernov, B.K., et al. (1971) Hyperforin, an Antibiotic from Hypericum perforatum L. Antibiotiki Kimioterapi, 16, 510-513. (In Russian)
[9]
Newman, D.J. and Cragg, G.M. (2020) Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019. JournalofNaturalProducts, 83, 770-803. https://doi.org/10.1021/acs.jnatprod.9b01285
[10]
Greeson, J.M., Sanford, B. and Monti, D.A. (2001) St. John’s Wort (Hypericum perforatum): A Review of the Current Pharmacological, Toxicological, and Clinical Literature. Psychopharmacology, 153, 402-414. https://doi.org/10.1007/s002130000625
[11]
Butterweck, V. and Schmidt, M. (2007) St. John’s Wort: Role of Active Compounds for Its Mechanism of Action and Efficacy. WienerMedizinischeWochenschrift, 157, 356-361. https://doi.org/10.1007/s10354-007-0440-8
[12]
Schempp, C.M., Pelz, K., Wittmer, A., Sch？pf, E. and Simon, J.C. (1999) Antibacterial Activity of Hyperforin from St John’s Wort, against Multiresistant Staphylococcus aureus and Gram-Positive Bacteria. The Lancet, 353, 2129-2132. https://doi.org/10.1016/s0140-6736(99)00214-7
[13]
Schempp, C.M., Kirkin, V., Simon-Haarhaus, B., Kersten, A., Kiss, J., Termeer, C.C., et al. (2002) Inhibition of Tumour Cell Growth by Hyperforin, a Novel Anticancer Drug from St. John’s Wort That Acts by Induction of Apoptosis. Oncogene, 21, 1242-1250. https://doi.org/10.1038/sj.onc.1205190
[14]
Brondz, I. (1979) Antibiotikumet “Hyperforin” og andre innholdsstoffer i drogen Hypericum perforatum L. Master’s Thesis, University of Oslo.
[15]
Brondz, I. (2012) Enhancement of the Immunity in AIDS and Other Immunocompromised Patients by Hyperforin, an Antibiotic from Hypericum perforatum L. 2nd ARIP European Conference on Antimicrobial Resistance & Infection Prevention, Vilnius, 4-5 October 2012, p. 61.
[16]
Brondz, I. and Brondz, A. (2012) Recent Enhancement of the Immunity in AIDS and Other Immunocompromised Patients by Hyperforin, an Antibiotic from Hypericum perforatum L. (In Vitro Model). Part I. JournalofBiophysicalChemistry, 3, 304-310. https://doi.org/10.4236/jbpc.2012.34037
[17]
Cardile, A., Zanrè, V., Campagnari, R., Asson, F., Addo, S.S., Orlandi, E., et al. (2023) Hyperforin Elicits Cytostatic/Cytotoxic Activity in Human Melanoma Cell Lines, Inhibiting Pro-Survival NF-κB, STAT3, AP1 Transcription Factors and the Expression of Functional Proteins Involved in Mitochondrial and Cytosolic Metabolism. InternationalJournalofMolecularSciences, 24, Article 1263. https://doi.org/10.3390/ijms24021263
[18]
Gartner, M., Müller, T., Simon, J.C., Giannis, A. and Sleeman, J.P. (2005) Aristoforin, a Novel Stable Derivative of Hyperforin, Is a Potent Anticancer Agent. ChemBioChem, 6, 171-177. https://doi.org/10.1002/cbic.200400195
[19]
Kacerovská, D., Pizinger, K., Majer, F. and ？míd, F. (2008) Photodynamic Therapy of Nonmelanoma Skin Cancer with Topical Hypericumperforatum Extract—A Pilot Study. PhotochemistryandPhotobiology, 84, 779-785. https://doi.org/10.1111/j.1751-1097.2007.00260.x
[20]
Osborn, E.M. (1943) On the Occurrence of Antibacterial Substances in Green Plants. British Journal of Experimental Pathology, 24, 227-231.
[21]
European Medicines Agency (2022) European Union Herbal Monograph on Hypericum perforatum L., Herba (Revision 1). European Medicines Agency. https://www.ema.europa.eu/documents/herbal-monograph/final-european-union-herbal-monograph-hypericum-perforatum-l-herba-revision-1_en.pdf
[22]
Volosovets, P.S. (1964) Microflora of Suppurative Wounds and the Quantitative Changes of the Microflora due to the Effect of Treatment with Amanine and Novoimanine. Mikrobiologichnyi Zhurnal, 26, 60-65.
[23]
Volosovets, P.S. (1986) The Effect of Novoimanine on the Course of Experimental Staphy-Lococcal Sepsis. Mikrobiologichnyi Zhurnal, 48, 60-64.
[24]
Bystrov, N.S., Chernov, B.K., Dobrynin, V.N. and Kolosov, M.N. (1975) The Structure of Hyperforin. TetrahedronLetters, 16, 2791-2794. https://doi.org/10.1016/s0040-4039(00)75241-5
[25]
Bystrov, N.S., Dobrynin, V.N., Kolosov, M.N., Chernov, B.K., Chervin, I.I. and Yakovlev, G.I. (1976) Stereokhimiya Antibiotika Hyperforina. Doklady Akademii Nauk SSSR, 226, 338-341. (In Russian)
[26]
Bystrov, N.S., Dobrynin, V.N., Kolosov, M.N., Popravko, S.A. and Chernov, B.K. (1978) Chemistry of Hyperforin. VI. General Chemical Characterization. Bioorganicheskaya Khimiya, 4, 791-797. (In Russian)
[27]
Bystrov, N.S., Dobrynin, V.N., Kolosov, M.N., Popravko, S.A. and Chernov, B.K. (1978) Chemistry of Hyperforin. VIII. Differentiation of the Side Chains. Bioorganicheskaya Khimiya, 4, 943-947. (In Russian)
[28]
Bystrov, N.S., Dobrynin, V.N., Kolosov, M.N., Popravko, S.A. and Chernov, B.K. (1978) Chemistry of Hyperforin. IX. The Structure of Hyperforin. Bioorganicheskaya Khimiya, 4, 948-955. (In Russian)
[29]
Bystrov, N.S., Gupta, S.R., Dobrynin, V.N., Kolosov, M.N., Chernov, B.K., Chervin, I.I., et al. (1976) Structure of the Antibiotic Hyperforin. Doklady Akademii Nauk SSSR, 226, 88-90. (In Russian)
[30]
Brondz, I., Greibrokk, T., Groth, P.A. and Aasen, A.J. (1982) The Relative Stereochemistry of Hyperforin—An Antibiotic from L. TetrahedronLetters, 23, 1299-1300. https://doi.org/10.1016/s0040-4039(00)87088-4
[31]
Brondz, I., Greibrokk, T., Groth, P., Aasen, A.J., Seip, R. and Brunvoll, J. (1983) The Absolute Configuration of Hyperforin, an Antibiotic from Hypericum perforatum L., Based on the Crystal Structure Determination of Its P-Bromobenzoate Ester. ActaChemicaScandinavica, 37, 263-265. https://doi.org/10.3891/acta.chem.scand.37a-0263
[32]
Shimizu, Y., Shi, S.L., Usuda, H., Kanai, M. and Shibasaki, M. (2010) Catalytic Asymmetric Total Synthesis of Ent‐Hyperforin. AngewandteChemieInternationalEdition, 49, 1103-1106. https://doi.org/10.1002/anie.200906678
[33]
Sparling, B.A., Moebius, D.C. and Shair, M.D. (2013) Enantioselective Total Synthesis of Hyperforin. JournaloftheAmericanChemicalSociety, 135, 644-647. https://doi.org/10.1021/ja312150d
[34]
Brondz, I. (2017) Super Antibiotics, Part IV. Hyperforin, Relative and Absolute Stereochemistry Elucidated by Gas-Chromatography Mass-Spectrometry with Supersonic Molecular Beams. InternationalJournalofAnalyticalMassSpectrometryandChromatography, 5, 70-85. https://doi.org/10.4236/ijamsc.2017.53005
[35]
Zanoli, P. (2004) Role of Hyperforin in the Pharmacological Activities of St. John’s Wort. CNSDrugReviews, 10, 203-218. https://doi.org/10.1111/j.1527-3458.2004.tb00022.x
[36]
Brondz, I., Fialkov, A.B. and Amirav, A. (2009) Analysis of Quinocide in Unprocessed Primaquine Diphosphate and Primaquine Diphosphate Tablets Using Gas Chromatography-Mass Spectrometry with Supersonic Molecular Beams. Journal of Chromatography A, 1216, 824-829. https://doi.org/10.1016/j.chroma.2008.11.043
[37]
Brondz, I. (2017) Super Antibiotics: Part III. Hyperforin, Revision of the Relative and Absolute Stereochemistry Presented by Bystrov et al. Voice of the Publisher, 3, 15-24. https://doi.org/10.4236/vp.2017.32002
[38]
Adam, P., Arigoni, D., Bacher, A. and Eisenreich, W. (2002) Biosynthesis of Hyperforin in Hypericum perforatum. Journal of Medicinal Chemistry, 45, 4786-4793. https://doi.org/10.1021/jm0209782
[39]
Brondz, I., Lingaas, E., Olssen, I. and Midtvedt, T. (1984) The Influence of Hyperforin on Phago-Cytosis of Escherichia coli by Human Polymorphonuclear Neutrophils in Vitro. 14th International Symposium on the Chemistry of Natural Products, Poznań, 9-14 July 1984, 590.
[40]
Brondz, I. (1987) Influence of Hyperforin Upon Phagocytic Functions in Human Polymorphonuclear Leucocytes. Fourth International Conference on Chemistry and Biotechnology of Biologically Active Natural Products, Budapest, 10-14 August 1987, p. 119.
[41]
Raczkiewicz, I., Rivière, C., Bouquet, P., Desmarets, L., Tarricone, A., Camuzet, C., et al. (2024) Hyperforin, the Major Metabolite of St. John’s Wort, Exhibits Pan-Coronavirus Antiviral Activity. FrontiersinMicrobiology, 15, Article ID: 1443183. https://doi.org/10.3389/fmicb.2024.1443183
[42]
Sabarathinam, S. and Ganamurali, N. (2026) Hyperforin as a Non-Steroidal Modulator of the PXR-CYP3A4 Regulatory Axis: Mechanistic and Computational Insights into Xenobiotic Metabolism. TheJournalofSteroidBiochemistryandMolecularBiology, 256, Article 106886. https://doi.org/10.1016/j.jsbmb.2025.106886
[43]
Biber, A., Fischer, H., R？mer, A. and Chatterjee, S. (1998) Oral Bioavailability of Hyperforin from Hypericum Extracts in Rats and Human Volunteers. Pharmacopsychiatry, 31, 36-43. https://doi.org/10.1055/s-2007-979344
[44]
Friedemann, U. (1942) Blood-Brain Barrier. PhysiologicalReviews, 22, 125-145. https://doi.org/10.1152/physrev.1942.22.2.125
[45]
Pardridge, W.M. (2012) Drug Transport across the Blood-Brain Barrier. JournalofCerebralBloodFlow&Metabolism, 32, 1959-1972. https://doi.org/10.1038/jcbfm.2012.126
[46]
Mruk, D.D. and Cheng, C.Y. (2015) The Mammalian Blood-Testis Barrier: Its Biology and Regulation. EndocrineReviews, 36, 564-591. https://doi.org/10.1210/er.2014-1101
[47]
Verotta, L., Appendino, G., Bombardelli, E. and Brun, R. (2007) In Vitro Antimalarial Activity of Hyperforin, a Prenylated Acylphloroglucinol. A Structure-Activity Study. Bioorganic&MedicinalChemistryLetters, 17, 1544-1548. https://doi.org/10.1016/j.bmcl.2006.12.100
[48]
Brondz, I., Klein, U., Mantzilas, D., Ekeberg, D., Hvattum, E., Schultz, H., et al. (2005) Nature of the Main Contaminant in the Drug Primaquine Diphosphate: GC-MS Analysis. Asian Journal of Chemistry, 17, 1678-1688. https://asianpubs.org/index.php/ajchem/article/view/14090
[49]
Brondz, I., Mantzilas, D., Klein, U., Ekeberg, D., Hvattum, E., Lebedeva, M.N., et al. (2004) Nature of the Main Contaminant in the Anti Malaria Drug Primaquine Diphosphate: A Qualitative Isomer Analysis. JournalofChromatographyB, 800, 211-223. https://doi.org/10.1016/j.jchromb.2003.09.042
[50]
Hostanska, K., Reichling, J., Bommer, S., Weber, M. and Saller, R. (2003) Hyperforin a Constituent of St John’s Wort (Hypericum perforatum L.) Extract Induces Apoptosis by Triggering Activation of Caspases and with Hypericin Synergistically Exerts Cytotoxicity towards Human Malignant Cell Lines. European Journal of Pharmaceutics and Biopharmaceutics, 56, 121-132. https://doi.org/10.1016/s0939-6411(03)00046-8
[51]
Schempp, C.M., Simon-Haarhaus, B. and Simon, J.C. (2002) Phototoxic and Apoptosis-Inducing Capacity of Pseudohypericin. PlantaMedica, 68, 171-173. https://doi.org/10.1055/s-2002-20264
[52]
Lorusso, G., Vannini, N., Sogno, I., Generoso, L., Garbisa, S., Noonan, D.M., et al. (2009) Mechanisms of Hyperforin as an Anti-Angiogenic Angioprevention Agent. EuropeanJournalofCancer, 45, 1474-1484. https://doi.org/10.1016/j.ejca.2009.01.014
[53]
Schempp, C., Kiss, J., Kirkin, V., Averbeck, M., Simon-Haarhaus, B., Kremer, B., et al. (2005) Hyperforin Acts as an Angiogenesis Inhibitor in Vitro and in Vivo. PlantaMedica, 71, 999-1004. https://doi.org/10.1055/s-2005-871303
[54]
Albini, A., Tosetti, F., Benelli, R. and Noonan, D.M. (2005) Tumor Inflammatory Angiogenesis and Its Chemoprevention. CancerResearch, 65, 10637-10641. https://doi.org/10.1158/0008-5472.can-05-3473
[55]
Dona？, M., Dell’Aica, I., Pezzato, E., Sartor, L., Calabrese, F., Barbera, M.D., et al. (2004) Hyperforin Inhibits Cancer Invasion and Metastasis. CancerResearch, 64, 6225-6232. https://doi.org/10.1158/0008-5472.can-04-0280
[56]
Brahmachari, G. (2017) Discovery and Development of Neuroprotective Agents from Natural Products. Elsevier.
[57]
Li, X.X., Yan, Y., Zhang, J., Ding, K., Xia, C.Y., Pan, X.G., et al. (2023) Hyperforin: A Natural Lead Compound with Multiple Pharmacological Activities. Phytochemistry, 206, Article 113526. https://doi.org/10.1016/j.phytochem.2022.113526
