Hyperforin

Last updated
Hyperforin
Hyperforin2DACS.svg
Hyperforin3Dan2.gif
Clinical data
Dependence
liability 		None
Routes of
administration 		Oral
ATC code
  • none
Legal status
Legal status
  • UK: General sales list (GSL, OTC)
  • US: OTC
  • unscheduled in most countries, with the notable exception of Ireland (Rx-only) [1]
Pharmacokinetic data
Metabolism Hepatic and CYP3A & CYP2B
Identifiers
  • (1R,5S,6R,7S)-4-Hydroxy-6-methyl-1,3,7-tris(3-methylbut-2-en-1-yl)-6-(4-methylpent-3-en-1-yl)-5-(2-methylpropanoyl)bicyclo[3.3.1]non-3-ene-2,9-dion
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard 100.112.565 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C35H52O4
Molar mass 536.797 g·mol−1
3D model (JSmol)
Melting point 79–80 °C (174–176 °F)
Solubility in water 0.66 mg/mL (20 °C)
  • CC(C)C(=O)[C@@]21C(=O)[C@@](C[C@H](C\C=C(/C)C)[C@@]1(C)CC\C=C(/C)C)(C\C=C(/C)C)C(=O)C(\C\C=C(/C)C)=C2\O
  • InChI=1S/C35H52O4/c1-22(2)13-12-19-33(11)27(16-14-23(3)4)21-34(20-18-25(7)8)30(37)28(17-15-24(5)6)31(38)35(33,32(34)39)29(36)26(9)10/h13-15,18,26-27,38H,12,16-17,19-21H2,1-11H3/t27-,33+,34+,35-/m0/s1 Yes check.svgY
  • Key:IWBJJCOKGLUQIZ-HQKKAZOISA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Hyperforin is a phytochemical produced by some of the members of the plant genus Hypericum , notably Hypericum perforatum (St John's wort). [2] Hyperforin may be involved in the pharmacological effects of St. John's wort, [2] specifically in its antidepressant effects. [3] [4] [5]

Contents

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. [2] It accumulates in oil glands, pistils, and fruits, probably as a plant defensive compound. [6] 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. [3] [7] [8] 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. [3] [7] [8] This CO2 extraction is rather tricky still because typical 'supercritical' conditions extract less material whereas anything over 40 °C (100°F) will degrade hyperforin. [3] [7] [8] Other Hypericum species contain low amounts of hyperforin. [9]

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. [3] [4] [10] 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. [11] [12] A total synthesis of the non-natural hyperforin enantiomer was reported in 2010 which required approximately 50 synthetic transformations. [13] 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. [10]

Hyperforin is unstable in the presence of light and oxygen. [14] Frequent oxidized forms contain a C3 to C9 hemiketal/heterocyclic bridge or will form furan/pyran derivatives. [7] [8]

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. [15]

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. [16]

Pharmacodynamics

Hyperforin may be a constituent responsible for the antidepressant and anxiolytic properties of the extracts of St. John's wort. [2] [17] In vitro, it acted as a reuptake inhibitor of monoamines (MRI), including serotonin, norepinephrine, dopamine, and of GABA and glutamate, with IC50 values of 0.05-0.10 μg/mL for all compounds, with the exception of glutamate, which is in the 0.5 μg/mL range. [18] In other laboratory studies, hyperforin induced cytochrome P450 enzymes CYP3A4 and CYP2C9 by binding to and activating the pregnane X receptor. [19]

Reuptake Inhibition
Neurotransmitter IC50 (nanomoles) [18]
Norepinephrine80 ± 24
Dopamine102 ± 19
GABA184 ± 41
5-HT205 ± 45
Glutamate829 ± 687
Choline8500
Binding affinity (human receptors)
Receptor Ki (nanomoles)
D1 595.8 [20]

Hyperforin Biosynthesis

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 formed 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. [21]

Proposed Hyperforin Biosynthesis.pdf

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. [22] [23]

See also

Related Research Articles

An anxiolytic is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxiety disorders and their related psychological and physical symptoms.

<i>Hypericum perforatum</i> Flowering plant in the St Johns wort family Hypericaceae

Hypericum perforatum, commonly known as St John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus Hypericum. It is a perennial that grows up to one meter tall, with many yellow flowers that have conspicuous black glands around their edges, long stamens, and three pistils. Probably a hybrid between close relatives H. attenuatum and H. maculatum that originated in Siberia, the species now has a cosmopolitan distribution. It is native to temperate regions across Eurasia and North Africa, and has been introduced to East Asia, Australia, New Zealand, and parts of North and South America. In many areas where it is not native, H. perforatum is considered a noxious weed. It densely covers open areas to the exclusion of native plants, and is poor grazing material. As such, methods for biocontrol have been introduced in an attempt to slow or reverse the spread of the species.

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<i>Hypericum</i> Genus of flowering plants known as St. Johns worts

Hypericum is a genus of flowering plants in the family Hypericaceae. The genus has a nearly worldwide distribution, missing only from tropical lowlands, deserts and polar regions. Many Hypericum species are regarded as invasive species and noxious weeds. All members of the genus may be referred to as St. John's wort, and some are known as goatweed. The white or pink flowered marsh St. John's worts of North America and eastern Asia are generally accepted as belonging to the separate genus TriadenumRaf.

<i>Hypericum calycinum</i> Species of flowering plant in the St Johns wort family Hypericaceae

Hypericum calycinum is a species of prostrate or low-growing shrub in the flowering plant family Hypericaceae. Widely cultivated for its large yellow flowers, its names as a garden plant include Rose-of-Sharon in Britain and Australia, and Aaron's beard, great St-John's wort, creeping St. John's wort and Jerusalem star. Grown in Mediterranean climates, widely spread in the Strandja Mountains along the Bulgarian and Turkish Black Sea coast.

<span class="mw-page-title-main">Serotonin–norepinephrine reuptake inhibitor</span> Class of antidepressant medication

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<span class="mw-page-title-main">Hypericin</span> Chemical compound

Hypericin is a naphthodianthrone, an anthraquinone derivative which, together with hyperforin, is one of the principal active constituents of Hypericum. Hypericin is believed to act as an antibiotic, antiviral and non-specific kinase inhibitor. Hypericin may inhibit the action of the enzyme dopamine β-hydroxylase, leading to increased dopamine levels, although thus possibly decreasing norepinephrine and epinephrine.

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<span class="mw-page-title-main">Adhyperforin</span> Chemical compound

Adhyperforin is a phytochemical found in the members of the plant genus Hypericum including St. John's Wort. It has a very similar pharmacological profile to hyperforin and acts as a TRPC6 ion channel activator, thereby inhibiting the reuptake of various neurotransmitters including serotonin, norepinephrine, dopamine, GABA, and glutamate. Adhyperforin is found in St. John's Wort in levels approximately 1/10 those of hyperforin.

<i>Hypericum olympicum</i> Species of flowering plant in the St Johns wort family Hypericaceae

Hypericum olympicum, commonly known as the Mount Olympus St. John's wort, is a species of flowering plant in the family Hypericaceae found in the Balkans and Turkey and introduced to western Europe. It has been widely cultivated for centuries because of its large, showy flowers, which are far larger than those of most other species in Hypericum.

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<span class="mw-page-title-main">Selective serotonin reuptake inhibitor</span> Class of antidepressant medication

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<span class="mw-page-title-main">PPPA (drug)</span> Chemical compound

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<span class="mw-page-title-main">Pseudohypericin</span> Chemical compound

Pseudohypericin is an aromatic polycyclic dione that is very closely related to hypericin. It is found most commonly in the St. John's wort family of plants, namely in Hypericum perforatum. In preliminary studies in animal models, pseudohypericin has shown antiviral effects. It may also contribute to the potential antidepressant effect of Hypericum perforatum extracts.

References

  1. ↑ St John's Wort available again Archived 2020-08-02 at the Wayback Machine . Irishhealth.com (2015-10-13). Retrieved on 2020-02-11.
  2. 1 2 3 4 "Hyperforin". PubChem, US National Library of Medicine. 8 September 2018. Retrieved 13 September 2018.
  3. 1 2 3 4 5 Gaid M, Biedermann E, Füller J, Haas P, Behrends S, Krull R, et al. (May 2018). "Biotechnological production of hyperforin for pharmaceutical formulation". European Journal of Pharmaceutics and Biopharmaceutics. 126: 10–26. doi:10.1016/j.ejpb.2017.03.024. PMID   28377273. S2CID   4701643.
  4. 1 2 Ciochina R, Grossman RB (September 2006). "Polycyclic polyprenylated acylphloroglucinols". Chemical Reviews. 106 (9): 3963–3986. doi:10.1021/cr0500582. PMID   16967926.
  5. ↑ Roz N, Rehavi M (October 2004). "Hyperforin depletes synaptic vesicles content and induces compartmental redistribution of nerve ending monoamines". Life Sciences. 75 (23): 2841–2850. doi:10.1016/j.lfs.2004.08.004. PMID   15464835.
  6. ↑ Beerhues L (October 2006). "Hyperforin". Phytochemistry. 67 (20): 2201–2207. Bibcode:2006PChem..67.2201B. doi:10.1016/j.phytochem.2006.08.017. PMID   16973193.
  7. 1 2 3 4 Vajs V, Vugdelija S, Trifunović S, Karadzić I, Juranić N, Macura S, Milosavljević S (July 2003). "Further degradation product of hyperforin from Hypericum perforatum (St John's Wort)". Fitoterapia. 74 (5): 439–444. doi:10.1016/S0367-326X(03)00114-X. PMID   12837358.
  8. 1 2 3 4 Verotta L, Appendino G, Belloro E, Jakupovic J, Bombardelli E (May 1999). "Furohyperforin, a prenylated phloroglucinol from st. John's wort (Hypericumperforatum)". Journal of Natural Products. 62 (5): 770–772. doi:10.1021/np980470v. PMID   10346967.
  9. ↑ Smelcerovic A, Spiteller M (March 2006). "Phytochemical analysis of nine Hypericum L. species from Serbia and the F.Y.R. Macedonia". Die Pharmazie. 61 (3): 251–252. PMID   16599273.
  10. 1 2 Sparling BA, Moebius DC, Shair MD (January 2013). "Enantioselective total synthesis of hyperforin". Journal of the American Chemical Society (Submitted manuscript). 135 (2): 644–647. doi:10.1021/ja312150d. PMID   23270309.
  11. ↑ Bystrov NS, Gupta S, Dobrynin VN, Kolosov MN, Chernov BK (January 1976). "[Structure of the antibiotic hyperforin]". Doklady Akademii Nauk SSSR (in Russian). 226 (1): 88–90. PMID   1248360.
  12. ↑ Bystrov NS, Chernov BK, Dobrynin VN, Kolosov MN (1975). "[The structure of hyperforin]". Tetrahedron Letters. 16 (32): 2791–2794. doi:10.1016/S0040-4039(00)75241-5.
  13. ↑ Shimizu Y, Shi SL, Usuda H, Kanai M, Shibasaki M (February 2010). "Catalytic asymmetric total synthesis of ent-hyperforin". Angewandte Chemie. 49 (6): 1103–1106. doi: 10.1002/anie.200906678 . PMID   20063336.
  14. ↑ Liu F, Pan C, Drumm P, Ang CY (February 2005). "Liquid chromatography-mass spectrometry studies of St. John's wort methanol extraction: active constituents and their transformation". Journal of Pharmaceutical and Biomedical Analysis. 37 (2): 303–312. doi:10.1016/j.jpba.2004.10.034. PMID   15708671.
  15. ↑ Biber A, Fischer H, Römer A, Chatterjee SS (June 1998). "Oral bioavailability of hyperforin from hypericum extracts in rats and human volunteers". Pharmacopsychiatry. 31 (Suppl 1): 36–43. doi:10.1055/s-2007-979344. PMID   9684946. S2CID   24700980.
  16. ↑ Schulz HU, Schürer M, Bässler D, Weiser D (2005). "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". Arzneimittel-Forschung. 55 (1): 15–22. doi:10.1055/s-0031-1296820. PMID   15727160. S2CID   6880438.
  17. ↑ Newall CA, Barnes J, Anderson LR (2002). Herbal medicines: a guide for healthcare professionals. London: Pharmaceutical Press. ISBN   978-0-85369-474-8.
  18. 1 2 Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A, Müller WE (1998). "Hyperforin as a possible antidepressant component of hypericum extracts". Life Sciences. 63 (6): 499–510. doi:10.1016/S0024-3205(98)00299-9. PMID   9718074.
  19. ↑ Moore LB, Goodwin B, Jones SA, Wisely GB, Serabjit-Singh CJ, Willson TM, et al. (June 2000). "St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor". Proceedings of the National Academy of Sciences of the United States of America. 97 (13): 7500–7502. Bibcode:2000PNAS...97.7500M. doi: 10.1073/pnas.130155097 . PMC   16574 . PMID   10852961.
  20. ↑ "Hyperforin". BindingDB. Retrieved 5 March 2015.
  21. ↑ Rizzo P, Altschmied L, Ravindran BM, Rutten T, D'Auria JC (October 2020). "The Biochemical and Genetic Basis for the Biosynthesis of Bioactive Compounds in Hypericum Perforatum L., One of the Largest Medicinal Crops in Europe". Genes. 11 (10): 1210. doi: 10.3390/genes11101210 . PMC   7602838 . PMID   33081197.
  22. ↑ Ng QX, Venkatanarayanan N, Ho CY (March 2017). "Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis". Journal of Affective Disorders. 210: 211–221. doi:10.1016/j.jad.2016.12.048. PMID   28064110. 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.
  23. ↑ Cui YH, Zheng Y (2016). "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". Neuropsychiatric Disease and Treatment. 12: 1715–1723. doi: 10.2147/NDT.S106752 . PMC   4946846 . PMID   27468236. 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.
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