hyperforin

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. It accumulates in oil glands, pistils, and fruits, probably as a plant defensive compound.{{cite journal | vauthors = Beerhues L | title = Hyperforin | journal = Phytochemistry | volume = 67 | issue = 20 | pages = 2201–2207 | date = October 2006 | pmid = 16973193 | doi = 10.1016/j.phytochem.2006.08.017 | bibcode = 2006PChem..67.2201B }} 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.{{cite journal | vauthors = Vajs V, Vugdelija S, Trifunović S, Karadzić I, Juranić N, Macura S, Milosavljević S | title = Further degradation product of hyperforin from Hypericum perforatum (St John's Wort) | journal = Fitoterapia | volume = 74 | issue = 5 | pages = 439–444 | date = July 2003 | pmid = 12837358 | doi = 10.1016/S0367-326X(03)00114-X }}{{cite journal | vauthors = Verotta L, Appendino G, Belloro E, Jakupovic J, Bombardelli E | title = Furohyperforin, a prenylated phloroglucinol from st. John's wort (Hypericumperforatum) | journal = Journal of Natural Products | volume = 62 | issue = 5 | pages = 770–772 | date = May 1999 | pmid = 10346967 | doi = 10.1021/np980470v }} 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. This CO₂ extraction is rather tricky still because typical 'supercritical' conditions extract less material whereas anything over 40 °C (100 °F) will degrade hyperforin. Other Hypericum species contain low amounts of hyperforin.{{cite journal | vauthors = Smelcerovic A, Spiteller M | title = Phytochemical analysis of nine Hypericum L. species from Serbia and the F.Y.R. Macedonia | journal = Die Pharmazie | volume = 61 | issue = 3 | pages = 251–252 | date = March 2006 | pmid = 16599273 }}

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. The structure of hyperforin was elucidated by a research group from the Shemyakin Institute of Bio-organic Chemistry (USSR Academy of Sciences in Moscow) and published in 1975.{{cite journal | vauthors = Bystrov NS, Gupta S, Dobrynin VN, Kolosov MN, Chernov BK | title = [Structure of the antibiotic hyperforin] | language = ru | journal = Doklady Akademii Nauk SSSR | volume = 226 | issue = 1 | pages = 88–90 | date = January 1976 | pmid = 1248360 }}{{cite journal |vauthors=Bystrov NS, Chernov BK, Dobrynin VN, Kolosov MN |title=[The structure of hyperforin] |journal=Tetrahedron Letters |volume=16 |issue=32 |pages=2791–2794 |year=1975 |doi=10.1016/S0040-4039(00)75241-5 }} A total synthesis of the non-natural hyperforin enantiomer was reported in 2010 which required approximately 50 synthetic transformations.{{cite journal | vauthors = Shimizu Y, Shi SL, Usuda H, Kanai M, Shibasaki M | title = Catalytic asymmetric total synthesis of ent-hyperforin | journal = Angewandte Chemie | volume = 49 | issue = 6 | pages = 1103–1106 | date = February 2010 | pmid = 20063336 | doi = 10.1002/anie.200906678 | doi-access = free }} 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.{{cite journal | vauthors = Sparling BA, Moebius DC, Shair MD | title = Enantioselective total synthesis of hyperforin | journal = Journal of the American Chemical Society | volume = 135 | issue = 2 | pages = 644–647 | date = January 2013 | pmid = 23270309 | doi = 10.1021/ja312150d | url = http://nrs.harvard.edu/urn-3:HUL.InstRepos:12563735 | type = Submitted manuscript }}

Hyperforin is unstable in the presence of light and oxygen.{{cite journal | vauthors = Liu F, Pan C, Drumm P, Ang CY | title = Liquid chromatography-mass spectrometry studies of St. John's wort methanol extraction: active constituents and their transformation | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 37 | issue = 2 | pages = 303–312 | date = February 2005 | pmid = 15708671 | doi = 10.1016/j.jpba.2004.10.034 }} Frequent oxidized forms contain a C3 to C9 hemiketal/heterocyclic bridge or will form furan/pyran derivatives.

Some pharmacokinetic data on hyperforin is available for an extract containing 5% hyperforin. Maximal plasma levels (C_max) in human volunteers were reached 3–4 hours after administration of an extract containing 14.8 mg hyperforin. Biological half-life (t_1/2) 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.{{cite journal | vauthors = Biber A, Fischer H, Römer A, Chatterjee SS | title = Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers | journal = Pharmacopsychiatry | volume = 31 | issue = Suppl 1 | pages = 36–43 | date = June 1998 | pmid = 9684946 | doi = 10.1055/s-2007-979344 | s2cid = 24700980 }}

In healthy male volunteers, 612 mg dry extract of St. John's wort produced hyperforin pharmacokinetics characterised by a half life of 19.64 hours.{{cite journal | vauthors = Schulz HU, Schürer M, Bässler D, Weiser D | title = Investigation of the bioavailability of hypericin, pseudohypericin, hyperforin and the flavonoids quercetin and isorhamnetin following single and multiple oral dosing of a hypericum extract containing tablet | journal = Arzneimittel-Forschung | volume = 55 | issue = 1 | pages = 15–22 | year = 2005 | pmid = 15727160 | doi = 10.1055/s-0031-1296820 | s2cid = 6880438 }}

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Hyperforin may be a constituent responsible for the antidepressant and anxiolytic properties of the extracts of St. John's wort.{{cite book | vauthors = Newall CA, Barnes J, Anderson LR |title=Herbal medicines: a guide for healthcare professionals |publisher=Pharmaceutical Press |location=London |year=2002 |isbn=978-0-85369-474-8 }} In vitro, it acted as a reuptake inhibitor of monoamines (MRI), including serotonin, norepinephrine, dopamine, and of GABA and glutamate, with IC₅₀ values of {{nobr|0.05–0.10 μg/mL}} for all compounds, with the exception of glutamate, which is in the {{nobr|0.5 μg/mL}} range.{{cite journal | vauthors = Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Müller WE | title = Hyperforin as a possible antidepressant component of hypericum extracts | journal = Life Sciences | volume = 63 | issue = 6 | pages = 499–510 | year = 1998 | pmid = 9718074 | doi = 10.1016/S0024-3205(98)00299-9 }} In other laboratory studies, hyperforin induced cytochrome P450 enzymes CYP3A4 and CYP2C9 by binding to and activating the pregnane X receptor.{{cite journal | vauthors = Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, Collins JL, Kliewer SA | display-authors = 6 | title = St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 13 | pages = 7500–7502 | date = June 2000 | pmid = 10852961 | pmc = 16574 | doi = 10.1073/pnas.130155097 | doi-access = free | bibcode = 2000PNAS...97.7500M }}

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Hyperforin is a polyprenylated acylphloroglucinol (PPAP) derivative with a pholoroisobutyrophenone bicyclic core. Isobutryl-CoA (17) has been determined to be one of the initial primary metabolite starter molecules in the biosynthesis of the hyperforin core structure. Isobutryl-CoA is derived from an a-ketoisovalerate intermediate (15). The bicyclic structure suggests that it has elements of meroterpenoid origin. The nucleus of hyperforin is formed in a sequence condensation of one molecule of isobutyryl-CoA and three molecules of malonyl-CoA, both catalyzed by Isobutyrophenone synthase. Type III PKS enzymes will catalyze the decarboxylative condensation of enzyme active sites to generate scaffolding.

These enzymes preferred a different substrate and did not produce identical products. The cell-free extracts from the cell cultures were incubated with isobutyryl-CoA and malonyl-CoA, phlorisobutyrophenone was formed (18). The enzymatic reaction was identified as BUS. PIVP is a similar function of enzyme in glandular hairs of hop cones. Two acylphloroglucinoal cores PICP and PIBP are formed by Claisen condensation but will differ in substrate and enzyme specificities. PIVP will use isovaleryl-CoA in the presence of an enzyme VSP, and PIBP will use isobutyryl-CoA in the presence of bus resulting in the production of adhyperforin and hyperforin.  

However, hyperforin is an easily degradable compound highly sensitive to heat and light in its powder form or within a solution, making it difficult to determine a true synthesis route for hyperforin making this synthesis route a possible route.{{cite journal | vauthors = Rizzo P, Altschmied L, Ravindran BM, Rutten T, D'Auria JC | title = The Biochemical and Genetic Basis for the Biosynthesis of Bioactive Compounds in Hypericum Perforatum L., One of the Largest Medicinal Crops in Europe | journal = Genes | volume = 11 | issue = 10 | pages = 1210 | date = October 2020 | pmid = 33081197 | pmc = 7602838 | doi = 10.3390/genes11101210 | doi-access = free }}

File:Proposed Hyperforin Biosynthesis.pdf

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.{{cite journal | vauthors = Ng QX, Venkatanarayanan N, Ho CY | title = Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis | journal = Journal of Affective Disorders | volume = 210 | pages = 211–221 | date = March 2017 | pmid = 28064110 | doi = 10.1016/j.jad.2016.12.048 | quote = 27 clinical trials with a total of 3808 patients were reviewed [...] For patients with mild-to-moderate depression, St John's wort has comparable efficacy and safety when compared to SSRIs. Follow-up studies carried out over a longer duration should be planned to ascertain its benefits. }}{{cite journal | vauthors = Cui YH, Zheng Y | title = A meta-analysis on the efficacy and safety of St John's wort extract in depression therapy in comparison with selective serotonin reuptake inhibitors in adults | journal = Neuropsychiatric Disease and Treatment | volume = 12 | pages = 1715–1723 | year = 2016 | pmid = 27468236 | pmc = 4946846 | doi = 10.2147/NDT.S106752 | quote = A total of 3,126 patients with depression were included. St John’s wort extract did not differ from SSRIs in clinical response, remission, and mean reduction in Hamilton Rating Scale for Depression score. [...] Both St John’s wort extract and SSRIs are effective in treating mild-to-moderate depression. St John’s wort extract is safer than SSRIs. | doi-access = free }}

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