Ingenol-3-angelate

Base Information

• Chemical Name: Ingenol-3-angelate
• CAS No.: 75567-37-2
• Deprecated CAS: 849146-39-0
• Molecular Formula: C25H34O6
• Molecular Weight: 430.541
• European Community (EC) Number: 688-125-2
• UNII: 7686S50JAH
• DSSTox Substance ID: DTXSID301025610
• Wikipedia: Ingenol_mebutate
• Wikidata: Q426386
• NCI Thesaurus Code: C48398
• Pharos Ligand ID: 9KJS29QNJ1D5
• Metabolomics Workbench ID: 64847
• ChEMBL ID: CHEMBL1863513
• Mol file: 75567-37-2.mol

Synonyms:Ingenol-3-angelate;3-Indolyl-b-D-galactopyranoside;(1S,4S,5S,6R,9R,10R,12R,14R)-5,6-Dihydroxy-7-(hydroxymethyl)-3,11,11,14-tetramethyl-15-oxotetracyclo[7.5.1.0^1,5.0^10,12]pentadeca-2,7-dien-4-yl (2Z)-2-methyl-2-butenoate;indican (glucoside);Ingenol mebutate;Indoxyl |A-D-galactopyranoside;3-O-angeloylingenol;ingenol 3-angelate;

Chemical Property of Ingenol-3-angelate

Chemical Property:

• Boiling Point: 576.9±50.0 °C(Predicted)
• PKA: 11.52±0.70(Predicted)
• PSA: 104.06000
• Density: 1.26±0.1 g/cm3(Predicted)
• LogP: 2.33230
• Storage Temp.: ?20°C
• Solubility.: DMSO: soluble15mg/mL, clear
• Water Solubility.: Soluble in 100% ethanol, DMSO, dichloromethane, and methanol. Insoluble in water.
• XLogP3: 2
• Hydrogen Bond Donor Count: 3
• Hydrogen Bond Acceptor Count: 6
• Rotatable Bond Count: 4
• Exact Mass: 430.23553880
• Heavy Atom Count: 31
• Complexity: 926

Purity/Quality:

98%,99%, ^*data from raw suppliers

Ingenol3-Angelate ^*data from reagent suppliers

Safty Information:

• Pictogram(s):  
• Hazard Codes: 

MSDS Files:

SDS file from LookChem

Useful:

• Canonical SMILES: CC=C(C)C(=O)OC1C(=CC23C1(C(C(=CC(C2=O)C4C(C4(C)C)CC3C)CO)O)O)C
• Isomeric SMILES: C/C=C(/C)\C(=O)O[C@H]1C(=C[C@@]23[C@@]1([C@@H](C(=C[C@H](C2=O)[C@H]4[C@H](C4(C)C)C[C@H]3C)CO)O)O)C
• Recent ClinicalTrials: Study Evaluating the Efficacy and Safety of 0.05% Ingenol Mebutate (Picato? 500) in the Treatment of Basal Cell Carcinoma
• Recent EU Clinical Trials: Investigations of local skin reactions and safety after combined treatment of basal cell carcinoma using ablative fractional laser and ingenol mebutate - an exloratory, prospective, open-label phase 2a trial.
• Clinical Use: Ingenol mebutate is the active ingredient in the sap from the Euphorbia peplus plant that has been used to treat a variety of skin lesions including warts, AKs, and NMSC. Recent clinical trials have demonstrated that two or three applica-tions of ingenol mebutate is effective in clearing AKs and BCCs. The efficacy of the treatment increased in a dose dependent manner with only mild dose dependent dermatological side effects, confirming that short term use of ingenol mebutate is safe when treating a variety of skin lesions. Ingenol mebutate is a diterpene ester which was approved in the US, EU, Austrailia, and Brazil for the treatment of actinic keratosis, a disease stage associated with sun exposure which can potentially develop into cancer. The drug, which is marketed by LEO Pharma A/S as Picato?, is administered as a topical gel (0.015%, 0.05%) which has been proven effective in treating face-, scalp-, and trunklocalized actinic keratosis in four randomized, double-blind, vehicle-controlled, multicenter studies. The drug exhibits mild side effects limited to application-site conditions (e. g. irritation, pain, pruritus), and no detectable concentrations of ingenol mebutate or two of its metabolites were found in blood samples.94 Traditionally used as a home remedy for various skin conditions, the ingenol mebutate, also referred to as ingenol 3-angelate, is the main active constituent of sap from the plant Euphorbia pelpus.95 From natural extractions, 17 kg of fresh E. pelpus afforded 7 g of ingenol 3-angelate as an oil, which upon further purification was deemed insufficient for process-scale production.
• Description: Ingenol mebutate (also known as PEP005) was approved in January 2012 by the US FDA for the topical treatment of actinic keratoses (AK). Ingenol mebutate also received approval in 2012 in the European Union, Australia, and Brazil for the same indication. Ingenol mebutate, a diterpene ester natural product, is the active agent in the sap of the plant Euphorbia peplus, which has long been used as a traditional remedy for skin lesions. Ingenol mebutate has a novel mechanism of action involving initial plasma membrane disruption, rapid loss of mitochondrial membrane potential, and cell death by primary necrosis within 1 h; a subsequent tumor-specific immune response results in antibodydependent cellular toxicity that eliminates residual cells. Ingenol mebutate is obtained by extraction from the dried, milled aerial parts of Euphorbia peplus followed by a series of purification steps.
• Uses: Ingenol 3-Angelate is used as a PKC activator, anticancer, and immunostimulant compound. It is also used to exhibits antileukemic activity, induces nuclear translocation of PKCδ, and induces apoptosis in acute myeloid leukemia (AML) cell lines and primary AML blast cells. Also displays antiproliferative effects and induces apoptosis in Colo205 cells. Ingenol 3-Angelate is known to exhibit antitumor activities which induces plasma membrane and mitochondrial disruption and necrotic cell death.

Technology Process of Ingenol-3-angelate

There total 22 articles about Ingenol-3-angelate which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 99.0%

Angelic acid (565-63-9) + (6S,6aR,7aR,9R,9aS,12S,12aR,12bR)-12,12a-dihydroxy-2,2,7,7,9,11-hexamethyl-4,6,6a,7,7a,8,9,12,12a,12b-decahydro-6,9a-methanocyclopenta[9,10]cyclopropa[5,6]cyclodeca[1,2-d][1,3]dioxin-13-one (77573-43-4) → ingenol-3-tigliate (1356187-27-3,849146-39-0) + ingenol mebutate (75567-37-2,849146-39-0)

Guidance literature:

With hydrogenchloride; water; In methanol; at 20 ℃; for 1h;

DOI:10.1055/s-0032-1317415

Reference yield: 91.1%

3-O-angeloyl-5,20-O-isopropylideneingenol (87980-68-5) → ingenol mebutate (75567-37-2,849146-39-0)

Guidance literature:

With hydrogenchloride; In methanol; water; at 20 ℃; for 4h;

DOI:10.1016/j.ejmech.2018.07.020

Reference yield: 40.0%

ingenol-20-(tert-butyldimethylsilyl)-ether-3-angelate (1356187-24-0) → ingenol mebutate (75567-37-2,849146-39-0)

Guidance literature:

With hydrogenchloride; methanol; water; In tetrahydrofuran; at 20 ℃; for 6.5h;

upstream raw materials:

Angelic acid

ingenol

(Z)-2-methyl-2-butenoic anhydride

3-O-angeloyl-5,20-O-isopropylideneingenol

Downstream raw materials:

ingenol

ingenol 20-acetate-3-angelate

3-O-angeloyl-5,20-O-isopropylideneingenol

Refernces

• 1、 Ohyoshi, Takayuki,Tamura, Yuki,Hayakawa, Ichiro,Hirai, Go,Miyazawa, Yamato,Funakubo, Shota,Sodeoka, Mikiko,Kigoshi, Hideo. "Total synthesis of natural derivatives and artificial analogs of 13-oxyingenol and their biological evaluation". . p. 11426 - 11437. Retrieved 2016/12/18.
• 2、 -. "PROCESS FOR THE PREPARATION OF INGENOL-3-ANGELATE FROM 20-DEOXY-INGENOL". Page/Page column 8. . Retrieved 2014/02/15.