Hyperforin

Occurrence

Hyperforin has only been found in significant amounts in Hypericum perforatum with other related species such as Hypericum calycinum containing lower levels of the phytochemical. The first natural extractions were done with ethanol and afforded a 7:1 yield of crude extract to phytochemical however, this technique produced a mixture of hyperforin and adhyperforin. The extraction technique has since been modernized using lipophilic liquid CO2 extraction to afford a 3:1 crude to phytochemical extraction which is then further purified away from adhyperforin.

Chemistry

Hyperforin is a prenylated phloroglucinol derivative and is a member of the Polycyclic polyprenylated acylphloroglucinol family, also known as the PPAP family. Hyperforin is a unique PPAP because it consists of a C8 quaternary stereocenter which was a synthetic challenge unlike other PPAP synthetic targets. A total synthesis of the non-natural hyperforin enantiomer was reported in 2010 which required approximately 50 synthetic transformations. In 2010, an enantioselective total synthesis of the correct enantiomer was disclosed. The retrosynthetic analysis was inspired by hyperforin's structural symmetry and biosynthetic pathway. The synthetic route undertaken generated a prostereogenic intermediate which then established the synthetically challenging C8 stereocenter and facilitated the stereochemical outcomes for the remainder of the synthesis.

Hyperforin is unstable in the presence of light and oxygen. Frequent oxidized forms contain a C3 to C9 hemiketal/heterocyclic bridge or will form furan/pyran derivatives.

Pharmacokinetics

Some pharmacokinetic data on hyperforin is available for an extract containing 5% hyperforin. Maximal plasma levels (Cmax) in human volunteers were reached 3–4 hours after administration of an extract containing 14.8 mg hyperforin. Biological half-life (t1/2) and mean residence time were 9 hours and 12 hours, respectively, with an estimated steady state plasma concentration of 100 ng/mL (approx. 180 nM) for 3 doses per day. Linear plasma concentrations were observed within a normal dosage range and no accumulation occurred.

In healthy male volunteers, 612 mg dry extract of St. John's wort produced hyperforin pharmacokinetics characterized by a half-life of 19.64 hours.

Pharmacodynamics

Hyperforin may be a constituent responsible for the antidepressant and anxiolytic properties of the extracts of St. John's wort. In vitro, it acted as a reuptake inhibitor of monoamines (MRI) (particularly of serotonin, norepinephrine, dopamine) and of GABA and glutamate, with IC50 values of for all compounds, with the exception of glutamate, which is in the range. In other laboratory studies, hyperforin induced cytochrome P450 enzymes CYP3A4 and CYP2C9 by binding to and activating the pregnane X receptor.

Biosynthesis

Current research focuses on understanding the biosynthesis of hyperforin and applying advanced techniques like omics, genome editing, and synthetic biology to enhance their pharmaceutical and medical uses.

It faces production challenges that biotechnological methods, such as specialized plant root cultures and microbial biosynthesis, are being developed to overcome for scalable and modifiable manufacturing.

File:Adhyperforin2DACS.svg|Adhyperforin File:Aristoforin2DACS2.svg|Aristoforin File:IDN54912DACS.svg|Hyperforin trimethoxybenzoate File:Tetrahydrohyperforin2DACS.svg|Tetrahydrohyperforin File:Hyperforinnicotinate2DACS.svg|Hyperforin nicotinate

Antidepressant research

Two meta-analyses of preliminary clinical trials evaluating the efficacy of St. John's wort for treating mild-to-moderate depression indicated a response similar to selective serotonin reuptake inhibitors and with better tolerance, although the long-term generalization of study results was limited by the short duration (4–12 weeks) of reviewed studies.

References

References

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