Tigilanol tiglate

Tigilanol tiglate (USAN;[1] ), sold under the brand name Stelfonta is a medication used to treat dogs with non-metastatic, skin-based (cutaneous) mast cell tumors (MCTs). The FDA is also approving Stelfonta to treat non-metastatic MCTs located under the dog's skin (subcutaneous), in particular areas of a dog's leg.[2] Stelfonta is injected directly into the MCT (intratumoral injection). Stelfonta works by activating a protein that spreads throughout the treated tumor, which disintegrates tumor cells.

Tigilanol tiglate
Clinical data
Trade namesStelfonta
Other namesEBC-46
License data
Routes of
administration		Injection
ATCvet code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Identifiers
IUPAC name
  • (1aR,1bR,1cS,2aR,3S,3aS,6aS,6bR,7R,8R,8aS)-3,3a,6b-Trihydroxy-2a-(hydroxymethyl)-1,1,5,7-tetramethyl-8a-{[(2S)-2-methylbutanoyl]oxy}-4-oxo-1a,1b,1c,2a,3,3a,4,6a,6b,7,8,8a-dodecahydro-1H-cyclopropa[5', 6']benzo[1',2':7,8]azuleno[5,6-b]oxiren-8-yl-(2E)-2-methyl-2-butenoate
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
Chemical and physical data
FormulaC30H42O10
Molar mass562.656 g·mol−1
3D model (JSmol)
SMILES
  • CCC(C)C(=O)O[C@@]12[C@@H](C1(C)C)[C@@H]3[C@H]4[C@](O4)([C@H]([C@]5([C@H]([C@]3([C@@H]([C@H]2OC(=O)/C(=C/C)/C)C)O)C=C(C5=O)C)O)O)CO
InChI
  • InChI=1S/C30H42O10/c1-9-13(3)23(33)38-21-16(6)28(36)17-11-15(5)20(32)29(17,37)25(35)27(12-31)22(39-27)18(28)19-26(7,8)30(19,21)40-24(34)14(4)10-2/h9,11,14,16-19,21-22,25,31,35-37H,10,12H2,1-8H3/b13-9+/t14?,16-,17+,18-,19-,21-,22+,25-,27+,28+,29-,30-/m1/s1 N
  • Key:YLQZMOUMDYVSQR-YUKITULJSA-N N
 NY (what is this?)  (verify)

It is a tiglien-3-on derivative, with a tigliane backbone. Since the substance is obtained by extraction, impurities with other tiglian-3-one derivatives are possible.

Initially, the synthesis was only used to confirm the structure and is possible via the Wender synthesis.[3] In 2022, the Wender group reported an efficient semi-synthesis of tigilanol tiglate from phorbol (12% overall yield over 12 steps).[4]

Tigilanol tiglate was approved for use in dogs in the European Union in January 2020.[5] It is indicated for the treatment of non-resectable, non-metastatic (WHO staging) subcutaneous mast cell tumors located at or distal to the elbow or the hock, and non-resectable, non metastatic cutaneous mast cell tumors in dogs.[5]

Research

Tigilanol tiglate is an experimental drug candidate being studied in phase I and II human trials by the Australian company Ecobiotics (specifically its drug discovery subsidiary Qbiotics) in partnership with MSD.[6] It was discovered through an automated screening process of natural products by selecting increasingly purified fractions of plant extracts, based on their ability to produce the desired activity profile. This is then followed by artificial synthesis of the isolated compound to confirm its chemical structure. Tigilanol tiglate is a phorbol ester which, along with other related compounds, acts as a protein kinase C regulator.[7]

The initial lead came from observation that marsupials found the seed of Fontainea picrosperma (blushwood) unpalatable due to an inflammatory chemical present in reasonably high concentrations. This was identified as 12-tigloyl-13-(2-methylbutanoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-1-tiglian-3-one.[8]

Tigilanol tiglate is an extract from blushwood berries of Queensland, Australia.[9]

References
  1. "United States Adopted Name (USAN) Drug Finder" (PDF). United States Adopted Names. American Medical Association. Retrieved 20 February 2017.
  2. "FDA Approves First Intratumoral Injection to Treat Non-Metastatic Mast Cell Tumors in Dogs". FDA. 20 November 2020.
  3. Wender PA, Kogen H, Lee HY, Munger JD, Wilhelm RS, Williams PD (1989). "Studies on tumor promoters. 8. The synthesis of phorbol". Journal of the American Chemical Society. 111 (24): 8957–8958. doi:10.1021/ja00206a050.
  4. Wender, Paul A.; Gentry, Zachary O.; Fanelli, David J.; Luu-Nguyen, Quang H.; McAteer, Owen D.; Njoo, Edward (2022-10-03). "Practical synthesis of the therapeutic leads tigilanol tiglate and its analogues". Nature Chemistry: 1–6. doi:10.1038/s41557-022-01048-2. ISSN 1755-4349.
  5. "Stelfonta EPAR". European Medicines Agency (EMA). 7 November 2019. Retrieved 13 May 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. "First patient dosed in QBiotics & MSD clinical trial collaboration for unresectable melanoma". qbiotics.com. 3 June 2021. Retrieved 2021-10-12.{{cite web}}: CS1 maint: url-status (link)
  7. Aitken A (1987). "The activation of protein kinase G by daphnane, ingenane and tigliane diterpenoid esters". Botanical Journal of the Linnean Society. 94 (1–2): 247–263. doi:10.1111/j.1095-8339.1987.tb01049.x.
  8. WO 2007070985, "Tiglian-3-one derivatives"
  9. Boyle GM, D'Souza MM, Pierce CJ, Adams RA, Cantor AS, Johns JP, et al. (2014). "Intra-lesional injection of the novel PKC activator EBC-46 rapidly ablates tumors in mouse models". PLOS ONE. 9 (10): e108887. Bibcode:2014PLoSO...9j8887B. doi:10.1371/journal.pone.0108887. PMC 4182759. PMID 25272271.


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