TITLE:
Hyperforin from Hypericum perforatum L.: Correct Stereochemistry, Structural Evidence, and Biological Activity
AUTHORS:
Larysa Karaliova, Ilia Brondz
KEYWORDS:
Hyperforin, Hypericum perforatum, Polyprenylated Acylphloroglucinol, Stereochemistry, X-Ray Crystallography, GC-MS with SMB, Biosynthesis, Biological Activity
JOURNAL NAME:
Journal of Biophysical Chemistry,
Vol.17 No.3,
August
31,
2026
ABSTRACT: 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.