Antiarigenin

Antiarigenin
Skeletal structure of antiarigenin
Names
IUPAC name
(3β,5β,12β)-3,5,12,14-Tetrahydroxy-19-oxo-card-20(22)-enolide
Identifiers
3D model (JSmol)
ChemSpider
  • InChI=1S/C23H32O7/c1-20-15(13-8-19(27)30-11-13)4-7-23(20,29)16-3-6-22(28)10-14(25)2-5-21(22,12-24)17(16)9-18(20)26/h8,12,14-18,25-26,28-29H,2-7,9-11H2,1H3/t14-,15+,16+,17-,18+,20-,21-,22-,23-/m0/s1
    Key: FMCCZSFBYFYVDN-XSGAPQDKSA-N
  • C[C@@]12[C@H](CC[C@@]1([C@@H]3CC[C@@]4(C[C@H](CC[C@@]4([C@H]3C[C@H]2O)C=O)O)O)O)C5=CC(=O)OC5
Properties
C23H32O7
Molar mass 420.502 g·mol−1
Appearance White to off-white crystalline solid
Melting point Decomposes above 240 °C
Poorly soluble
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Highly toxic cardiac poison
Lethal dose or concentration (LD, LC):
<0.1 mg/kg (mammalian, oral)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Antiarigenin is a highly toxic cardenolide aglycone found in the latex of Antiaris toxicaria (upas tree). As the steroid core of α-antiarin and β-antiarin glycosides, it has been used for centuries by indigenous peoples of Southeast Asia in blowdart arrow poisons. It functions as a potent Na+/K+-ATPase inhibitor and has shown potential to induce apoptosis in chemotherapy-resistant cancer cells through orphan nuclear receptor Nur77 modulation.

Natural occurrence

Antiarigenin serves as a chemotaxonomic marker for the genus Antiaris (Moraceae). A. toxicaria is a large deciduous tree native to tropical regions from West Africa through the Indian subcontinent and Southern China to Indonesia and Northern Australia. The tree's milky latex contains high concentrations of cardenolides, particularly in the bark, with lower amounts in seeds and leaves.

Antiarigenin is rarely stored freely; glycosyltransferase enzymes attach sugars, usually L-rhamnose or D-antiarose, to the C-3 hydroxyl group, forming the parent glycosides. Biosynthesis proceeds via the pregnane pathway, with phytosterol precursors undergoing side-chain cleavage, stereoselective reduction, specific hydroxylations, and oxidation of the C-19 methyl group to an aldehyde.

Chemical structure

Antiarigenin has a tetracyclic gonane nucleus with a cis–trans–cis ring fusion pattern. The A/B ring junction is cis-fused (5β-H), creating a molecular "kink" essential for binding to the cardiac glycoside receptor site on Na+/K+-ATPase. Key functional groups include four hydroxyl groups (C-3β, C-5β, C-12β, C-14β), a C-19 aldehyde (distinguishing it from digitoxigenin), and a butenolide (unsaturated γ-lactone) ring at C-17β. This places it in the strophanthidin class of cardenolides.

The structure is confirmed by NMR and X-ray crystallography. The 1H NMR shows a characteristic aldehyde proton at δH 9.8–10.5 ppm, while 13C NMR reveals the aldehyde carbon at ~208 ppm and lactone carbonyl at ~175 ppm.

Mechanism of action

Antiarigenin binds the Na+/K+-ATPase (sodium pump), stabilizing it in the phosphorylated E2-P conformation and blocking ion exchange. In cardiac myocytes, this raises intracellular calcium, producing a positive inotropic effect at therapeutic doses or cardiac arrest at toxic doses.

Antiarigenin shows isoform selectivity among Na+/K+-ATPase α-subunits, preferentially targeting the α3 isoform enriched in neurons and cardiac conduction tissue. This may explain prominent neurotoxicity in Antiaris poisoning.

A second mechanism involves Nur77 modulation. Antiarigenin triggers nuclear export of Nur77, which then binds Bcl-2 at the mitochondrial membrane, converting it from an anti-apoptotic to a pro-apoptotic protein. This leads to cytochrome c release and caspase activation, effective even in Bcl-2-overexpressing chemoresistant cancer cells.

Ethnobotany

Indigenous groups in Southeast Asia, notably the Dayak of Borneo, have used A. toxicaria latex in blowdart poisons (ipoh, tajum) for hunting and warfare. Preparation required careful dehydration to concentrate cardenolides without hydrolyzing heat-labile glycosidic bonds.

Antiaris latex was typically combined with Strychnos extracts containing strychnine and brucine. This synergy ensured rapid immobilization: antiarigenin caused cardiotoxicity while strychnine, a glycine receptor antagonist, induced tetanic convulsions.

See also

References

  1. ↑ Carter, C.A. (2013). "Antiproliferative Cardiac Glycosides from the Latex of Antiaris toxicaria". J. Nat. Prod. 76: 1838–1843. doi:10.1021/np4005147. PMID 24093516.
  2. 1 2 3 4 5 6 Carter, C.A.; Forsberg, L.S.; Xu, J.; Matainaho, T.; Kikuchi, H.; Clardy, J. (2013). "Antiproliferative Cardiac Glycosides from the Latex of Antiaris toxicaria". J. Nat. Prod. 76 (10): 1838–1843. doi:10.1021/np4005147. PMID 24093516.
  3. 1 2 Quisumbing, E. (1978). "Blowpipe dart poison in Borneo and the secret of its production: the latex of Antiaris toxicaria" (PDF). Retrieved 12 February 2026.
  4. 1 2 3 Lin, B.; Kolluri, S.K.; Lin, F. (2018). "Induction of apoptosis and suppression of tumor growth by Nur77-derived Bcl-2 converting peptide in chemoresistant lung cancer cells". Oncotarget. 9 (40): 26072–26085. PMC 5995251. PMID 29899852.
  5. 1 2 3 "Antiaris toxicaria". PROSEA – Plant Resources of South East Asia. Retrieved 12 February 2026.
  6. 1 2 3 Dai, H.F.; Gan, Y.J.; Que, D.M.; Wu, J.; Wen, Z.C.; Mei, W.L. (2010). "Cardiac Glycosides from Antiaris toxicaria with Potent Cardiotonic Activity". Planta Med. 76 (14): 1905–1907. doi:10.1055/s-0030-1250036. PMC 2917517. PMID 20533172.
  7. ↑ Li, S.; Chen, J.; Zhang, Y. (2025). "A high-quality chromosome-level genome assembly of Antiaris toxicaria". Sci Data. 12: 241. doi:10.1038/s41597-025-03682-9. PMC 11934813. PMID 38589421.
  8. ↑ Hložek, T.; Kuchař, M. (2021). "Structural Insights into the Interactions of Digoxin and Na+/K+-ATPase". Molecules. 26 (12): 3672. doi:10.3390/molecules26123672. PMC 8234910.
  9. ↑ Laursen, M.; Gregersen, J.L.; Yatime, L. (2015). "Structures and characterization of digoxin- and bufalin-bound Na+,K+-ATPase". Proc Natl Acad Sci USA. 112 (6): 1755–1760. doi:10.1073/pnas.1422997112. PMC 4330780.
  10. ↑ Katz, A.; Lifshitz, Y.; Bab-Dinitz, E. (2016). "Isoform specificity of cardiac glycosides binding to human Na+,K+-ATPase". Sci Rep. 6 29759. doi:10.1038/srep29759. PMC 4948948.
  11. 1 2 "Antiaris toxicaria (PROSEA)". Pl@ntUse. Retrieved 12 February 2026.