Voacangine

Last updated
Voacangine
Voacangine.svg
Voacangine molecule ball.png
Names
IUPAC name
12-Methoxyibogamine-18-carboxylic acid, methyl ester
Systematic IUPAC name
Methyl 17-ethyl-7-methoxy-3,13-diazapentacyclo[13.3.1.02,10.04,9.013,18] nonadeca-2(10),4,6,8-tetraene-1-carboxylate [1]
Other names
Methyl 12-methoxyibogamine-18-carboxylate
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.214.137 OOjs UI icon edit-ltr-progressive.svg
MeSH Voacangine
PubChem CID
UNII
  • InChI=1S/C22H28N2O3/c1-4-14-9-13-11-22(21(25)27-3)19-16(7-8-24(12-13)20(14)22)17-10-15(26-2)5-6-18(17)23-19/h5-6,10,13-14,20,23H,4,7-9,11-12H2,1-3H3/t13-,14+,20+,22-/m1/s1 X mark.svgN
    Key: MMAYTCMMKJYIAM-PHKAQXKASA-N X mark.svgN
  • O=C(OC)[C@@]43c2[nH]c1ccc(OC)cc1c2CCN5[C@H]3[C@H](C[C@H](C4)C5)CC
Properties
C22H28N2O3
Molar mass 368.477 g·mol−1
Melting point 136 to 137 °C (277 to 279 °F; 409 to 410 K)
log P 3.748
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Voacangine (12-methoxyibogamine-18-carboxylic acid methyl ester) is an alkaloid found predominantly in the root bark of the Voacanga africana tree, as well as in other plants such as Tabernanthe iboga , Tabernaemontana africana , Trachelospermum jasminoides , Tabernaemontana divaricata and Ervatamia yunnanensis . [2] [3] [4] [5] It is an iboga alkaloid which commonly serves as a precursor for the semi-synthesis of ibogaine. [6] It has been demonstrated in animals to have similar anti-addictive properties to ibogaine itself. [7] It also potentiates the effects of barbiturates. [8] Under UV-A and UV-B light its crystals fluoresce blue-green, and it is soluble in ethanol.

Contents

Pharmacology

Pharmacodynamics

Voacangine exhibits AChE inhibitory activity. [9] [10] Docking simulation reveals that it has inhibitory effect on VEGF2 kinase [11] and reduces angiogenesis. [12] [13] Like ibogaine, its a potent HERG blocker in vitro. [14] It also acts as antagonist to TRPM8 and TRPV1 receptor, but agonist of TRPA1. [15] [16]

Pharmacokinetics

The absolute bioavailability of voacangine is around 11–13%. [14]

Side effects

High doses of voacangine produce convulsions and asphyxia. [17]

Chemistry

Biosynthesis

The late-stage biosynthesis of (-)-voacangine in Tabernanthe iboga , a (-)-ibogamine-type alkaloid, has been elucidated via homology-guided transcriptome mining. [18] Suspected RNA transcripts involved in (-)-voacangine biosynthesis were identified via sequence homology to previously described enzymes comprising the (+)-catharanthine biosynthesis, [19] a (+)-ibogamine-type alkaloid from the taxonomically related plant Catharanthus roseus .

Ibogamine-type alkaloids are biosynthesized from the late stage intermediate stemmadenine acetate, a strictosidine-derived biosynthetic intermediate for a wide number of plant natural products. The biosynthesis of stemmadenine acetate has been characterized in C. roseus [19] but remains uncharacterized in T. iboga.

Schematic of the late-stage biosynthesis of (-)-voacangine in Tabernanthe iboga Late-stage voacangine biosynthesis.svg
Schematic of the late-stage biosynthesis of (-)-voacangine in Tabernanthe iboga

Conversion of stemmadenine acetate to (-)-voacangine in T. iboga involves five enzymes. First, stemmadenine acetate (1) is converted to precondylocarpine acetate (2) by one of three T. iboga precondylocarpine acetate synthases (TiPAS1/2/3), a flavin-dependent oxidase. Next, 2 is reduced to the enamine (3), dihydroprecondylocarpine acetate, by one of two NADPH-dependent T. iboga dihydroprecondylocarpine acetate synthase (TiDPAS1/2).

Up to this point, the biosynthetic path towards the (-)-ibogamine alkaloids and (+)-ibogamine alkaloids is identical. Stereochemical divergence occurs during the cyclization step, whereby T. iboga coronaridine synthase (TiCorS), a catharanthine synthase (CS) homologue, catalyzes a stereoselective formal Diels-Alder reaction on dehydrosecodine (4) to form coronaridine iminium (5). A proposed mechanism for dehydrosecodine formation from 3 involves iminium-formation/deacetylation, enamine-formation, and subsequent isomerization. Reduction of 5 to (-)-coronaridine (6) is proposed to be catalyzed by TiDPAS, although it is unclear if the reduction is actually enzymatic due to a lack of a reaction trial with only NADPH. [Note 1] After formation of 6, the substrate is then 10-hydroxylated by ibogamine 10-hydroxylase (I10H), a CYP450 enzyme, and subsequently 10-O-methylated by noribogaine-10-O-methyltransferase (N10OMT), a SAM dependent enzyme, [20] to form (-)-voacangine (7).

See also

Notes

  1. ↑ See supplementary figure 15 of the Farrow et al. paper, citation 18. After initial incubation with TiCorS, no trial was run with just NADPH.

Related Research Articles

<i>Tabernanthe iboga</i> Species of plant

Tabernanthe iboga (iboga) is an evergreen rainforest shrub native to Central Africa. A member of the Apocynaceae family indigenous to Gabon, the Democratic Republic of Congo, and the Republic of Congo, it is cultivated across Central Africa for its medicinal and other effects.

<span class="mw-page-title-main">Ibogaine</span> Psychoactive substance found in plants in the family Apocynaceae

Ibogaine is a naturally occurring psychoactive substance found in plants in the family Apocynaceae such as Tabernanthe iboga, Voacanga africana, and Tabernaemontana undulata. It is a psychedelic with dissociative properties.

<span class="mw-page-title-main">Indole alkaloid</span> Class of alkaloids

Indole alkaloids are a class of alkaloids containing a structural moiety of indole; many indole alkaloids also include isoprene groups and are thus called terpene indole or secologanin tryptamine alkaloids. Containing more than 4100 known different compounds, it is one of the largest classes of alkaloids. Many of them possess significant physiological activity and some of them are used in medicine. The amino acid tryptophan is the biochemical precursor of indole alkaloids.

<i>Voacanga africana</i> Species of tree

Voacanga africana is a small tree native to tropical Africa belonging to the family Apocynaceae that grows to 6 m (20 ft) in height and bears leaves that are up to 30 cm (12 in) in length. The yellow or white flowers are succeeded by paired, follicular, dehiscent fruit with a mottled green exocarp and a pulpy, yellow mesocarp surrounding the seeds. The plant contains alkaloids acting as CNS depressants and hypotensives

Strictosidine synthase (EC 4.3.3.2) is an enzyme in alkaloid biosynthesis that catalyses the condensation of tryptamine with secologanin to form strictosidine in a formal Pictet–Spengler reaction:

<span class="mw-page-title-main">Noribogaine</span> Principal psychoactive metabolite of the oneirogen ibogaine

Noribogaine, or 12-hydroxyibogamine, is the principal psychoactive metabolite of the oneirogen ibogaine. It is thought to be involved in the antiaddictive effects of ibogaine-containing plant extracts, such as Tabernanthe iboga.

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

Coronaridine, also known as 18-carbomethoxyibogamine, is an alkaloid found in Tabernanthe iboga and related species, including Tabernaemontana divaricata for which it was named.

<span class="mw-page-title-main">Ibogamine</span> Anti-convulsant, anti-addictive CNS stimulant alkaloid

Ibogamine is an anti-convulsant, anti-addictive, CNS stimulant alkaloid found in Tabernanthe iboga and Crepe Jasmine. Basic research related to how addiction affects the brain has used this chemical.

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

Tabernanthine is an alkaloid found in Tabernanthe iboga.

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

Voacamine, also known under the older names voacanginine and vocamine, is a naturally occurring dimeric indole alkaloid of the secologanin type, found in a number of plants, including Voacanga africana and Tabernaemontana divaricata. It is approved for use as an antimalarial drug in several African countries. Voacamine exhibits cannabinoid CB1 receptor antagonistic activity.

<i>Tabernaemontana divaricata</i> Species of plant

Tabernaemontana divaricata, commonly called pinwheel flower, crape jasmine, East India rosebay, and Nero's crown, is an evergreen shrub or small tree native to South Asia, Southeast Asia and China. In zones where it is not hardy it is grown as a house/glasshouse plant for its attractive flowers and foliage. The stem exudes a milky latex when broken, whence comes the name milk flower

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

Stemmadenine is a terpene indole alkaloid. Stemmadenine is believed to be formed from preakuammicine by a carbon-carbon bond cleavage. Cleavage of a second carbon-carbon bond is thought to form dehydrosecodine. The enzymes forming stemmadenine and using it as a substrate remain unknown to date. It is thought to be intermediate compound in many different biosynthetic pathways such as in Aspidosperma species. Many alkaloids are proposed to be produced through intermediate stemmadenine. Some of them are:

Iboga-type alkaloids are a set of monoterpene indole alkaloids comprising naturally occurring compounds found in Tabernanthe and Tabernaemontana, as well as synthetic structural analogs. Naturally occurring iboga-type alkaloids include ibogamine, ibogaine, tabernanthine, and other substituted ibogamines (see below). Many iboga-type alkaloids display biological activities such as cardiac toxicity and psychoactive effects, and some have been studied as potential treatments for drug addiction.

<span class="mw-page-title-main">Ibogaline</span> Alkaloid found in Tabernanthe iboga

Ibogaline is an alkaloid found in Tabernanthe iboga along with the related chemical compounds ibogaine, ibogamine, and other minor alkaloids. It is a relatively smaller component of Tabernanthe iboga root bark total alkaloids (TA) content. It is also present in Tabernaemontana species such as Tabernaemontana australis which shares similar ibogan-biosynthetic pathways. The percentage of ibogaline in T. iboga root bark is up to 15% TA with ibogaine constituting 80% of the alkaloids and ibogamine up to 5%.

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

Tabernaemontanine is a naturally occurring monoterpene indole alkaloid found in several species in the genus Tabernaemontana including Tabernaemontana divaricata.

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

Dregamine is a naturally occurring monoterpene indole alkaloid found in several species in the genus Tabernaemontana including Ervatamia hirta and Tabernaemontana divaricata.

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

Conophylline is a autophagy inducing vinca alkaloid found in several species of Tabernaemontana including Ervatamia microphylla and Tabernaemontana divaricata. Among its many functional groups is an epoxide: the compound where that ring is replaced with a double bond is called conophyllidine and this co-occurs in the same plants.

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

Vobasine is a naturally occurring monoterpene indole alkaloid found in several species in the genus Tabernaemontana including Tabernaemontana divaricata.

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

Voacristine is a indole alkaloid occurring in Voacanga and Tabernaemontana genus. It is also an iboga type alkaloid.

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

Conopharyngine is the major alkaloid present in the leaves and stem-bark of Tabernaemontana pachysiphon and Conopharyngia durissima. It is closely related voacangine and coronaridine. Conopharyngine pseudoindoxyl, a derivative of it, is also found in the same plant Tabernaemontana pachysiphon.

References

  1. ↑ "Compound Report Card CHEMBL182120 - Voacangine". ChEMBL.
  2. ↑ Patel, M. B.; Miet, C.; Poisson, J. (1967). "Alkaloids of some African Tabernaemontana". Annales Pharmaceutiques Françaises. 25 (5): 379–384. PMID   5611538.
  3. ↑ Fatima, T.; Ijaz, S.; Crank, G.; Wasti, S. (1987). "Indole Alkaloids from Trachelospermum jasminoides". Planta Medica. 53 (1): 57–59. doi:10.1055/s-2006-962620. PMID   17268963. S2CID   910492.
  4. ↑ Liu, G.; Liu, X.; Feng, X. Z. (1988). "Ervayunine: A New Indole Alkaloid from Ervatamia yunnanensis". Planta Medica. 54 (6): 519–521. doi:10.1055/s-2006-962535. PMID   3212080. S2CID   84629414.
  5. ↑ Jenks, C. W. (2002). "Extraction Studies of Tabernanthe iboga and Voacanga africana". Natural Product Letters. 16 (1): 71–76. doi:10.1080/1057563029001/4881. PMID   11942686. S2CID   23390825.
  6. ↑ USpatent 2813873,"Derivatives of the Ibogaine Alkaloids",issued 1957-11-19
  7. ↑ Tsing Hua (January 28, 2006). "Antiaddictive Indole Alkaloids in Ervatamia yunnanensis and their Bioactivity". Academic Journal of Second Military Medical University. Archived from the original on February 13, 2012. Retrieved August 9, 2008.
  8. ↑ "Unknown" (PDF).[ permanent dead link ]
  9. ↑ VIEIRA I, MEDEIROS W, MONNERAT C, SOUZA J, MATHIAS L, BRAZ-FILHO R, PINTO A, SOUSA P, REZENDE C, EPIFANIO R (2008). "Two fast screening methods (GC-MS and TLC-ChEI assay) for rapid evaluation of potential anticholinesterasic indole alkaloids in complex mixtures" (PDF). Annals of the Brazilian Academy of Sciences. 80 (3): 419–426. doi:10.1590/s0001-37652008000300003. ISSN   0001-3765. PMID   18797794. Archived from the original (PDF) on 2020-02-19.
  10. ↑ Andrade MT, Lima JA, Pinto AC, Rezende CM, Carvalho MP, Epifanio RA (June 2005). "Indole alkaloids from Tabernaemontana australis (Muell. Arg) Miers that inhibit acetylcholinesterase enzyme". Bioorganic & Medicinal Chemistry . 13 (12): 4092–5. doi:10.1016/j.bmc.2005.03.045. PMID   15911323.
  11. ↑ Kim Y, Sugihara Y, Kim TY, Cho SM, Kim JY, Lee JY, Yoo JS, Song D, Han G, Rezeli M, Welinder C, Appelqvist R, Marko-Varga G, Kwon HJ (March 2020). "Identification and Validation of VEGFR2 Kinase as a Target of Voacangine by a Systematic Combination of DARTS and MSI". Biomolecules . 10 (4): 508. doi: 10.3390/biom10040508 . PMC   7226133 . PMID   32230857.
  12. ↑ Kim Y, Jung HJ, Kwon HJ (January 2012). "A natural small molecule voacangine inhibits angiogenesis both in vitro and in vivo". Biochemical and Biophysical Research Communications . 417 (1): 330–4. doi:10.1016/j.bbrc.2011.11.109. PMID   22155252.
  13. ↑ "Antiaddictive Indole Alkaloids in Ervatamia yunnanensis and their Bioactivity". Academic Journal of Second Military Medical University. January 28, 2006.
  14. 1 2 Mair CE, de Miranda Silva C, Grienke U, Kratz JM, Carreño F, Zimmermann ES, de Araújo BV, Dalla Costa T, Rollinger JM (July 2016). "Pharmacokinetics of hERG Channel Blocking Voacangine in Wistar Rats Applying a Validated LC-ESI-MS/MS Method". Planta Medica . 82 (11–12): 1030–8. doi:10.1055/s-0042-107800. PMID   27257769. S2CID   24504763.
  15. ↑ Terada Y, Horie S, Takayama H, Uchida K, Tominaga M, Watanabe T (February 2014). "Activation and inhibition of thermosensitive TRP channels by voacangine, an alkaloid present in Voacanga africana, an African tree". Journal of Natural Products . 77 (2): 285–97. doi:10.1021/np400885u. PMID   24484240.
  16. ↑ Lo MW, Matsumoto K, Iwai M, Tashima K, Kitajima M, Horie S, Takayama H (January 2011). "Inhibitory effect of Iboga-type indole alkaloids on capsaicin-induced contraction in isolated mouse rectum". Journal of Natural Medicines . 65 (1): 157–65. doi:10.1007/s11418-010-0478-6. PMID   21042867. S2CID   25706616.
  17. ↑ "Erowid Voacanga africana Vault : Info #1".
  18. ↑ Farrow, Scott C.; Kamileen, Mohamed O.; Caputi, Lorenzo; Bussey, Kate; Munday, Julia E. A.; McAtee, Rory C.; Stephenson, Corey R. J.; O'Connor, Sarah E. (31 July 2019). "Biosynthesis of an Anti-Addiction Agent from the Iboga Plant". Journal of the American Chemical Society. 141 (33): 12979–12983. doi:10.1021/jacs.9b05999. PMC   6706869 . PMID   31364847.
  19. 1 2 Qu, Yang; Easson, Micahel E. A. M.; Simionescu, Razvan; Hajicek, Josef; Thamm, Antje M. K.; Salim, Vonny; De Luca, Vicenzo (March 6, 2018). "Solution of the multistep pathway for assembly of corynanthean, strychnos, iboga, and aspidosperma monoterpenoid indole alkaloids from 19E-geissoschizine". Proceedings of the National Academy of Sciences. 115 (12): 3180–3185. Bibcode:2018PNAS..115.3180Q. doi: 10.1073/pnas.1719979115 . PMC   5866588 . PMID   29511102.
  20. ↑ Farrow, Scott C.; Kamileen, Mohamed O.; Meades, Jessica; Ameyaw, Belinda; Xiao, Youli; O'Connor, Sarah E. (September 7, 2018). "Cytochrome P450 and O-methyltransferase catalyze the final steps in the biosynthesis of the anti-addictive alkaloid ibogaine from Tabernanthe iboga". J Biol Chem. 293 (36): 13821–13833. doi: 10.1074/jbc.RA118.004060 . PMC   6130943 . PMID   30030374.
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