75567-37-2 Usage
Ingenol mebutate
Ingenol mebutate (PicatoTM, Leo Pharma), a macrocyclic diterpene ester, is the active constituent in the sap of Euphorbia peplus. Commonly known as radium weed, petty spurge, or milkweed, E. peplus has been used for centuries as a traditional remedy for cutaneous conditions including skin cancer.
Owing to a substantially shorter course of treatment (2-3 days) and duration of local cutaneous reaction, ingenol mebutate offers an appealing alternative to other topical agents used for the treatment of actinic keratoses.
Mechanism of action
Ingenol mebutate has a dual mechanism of action. Ingenol mebutate first induces rapid and direct cell death within hours of application followed by an acute inflammatory response that eliminates residual tumor cells.
In vitro and in vivo studies on B16 mouse melanoma cells exposed to ingenol mebutate revealed disruption of the cell membrane, loss of mitochondrial membrane potential, and mitochondrial swelling resulting in rapid primary necrosis. As a result of the rapid destruction of tumor cells, a treatment duration of 2–3 days is sufficient. Unlike other anti-cancer agents, ingenol mebutate does not trigger apoptosis, and thus the development of apoptosis resistance in tumor cells is unlikely to compromise its activity.
Following the initial cell necrosis, an acute inflammatory response occurs. Ingenol mebutate activates protein kinase c resulting in the release of pro-inflammatory cyto-kines (IL-1B, IL-8, TNF-alpha), the production of tumor-specific antibodies, an enhanced endothelial adhesion molecule expression, and a substantial infiltration of neutro-phils which generate tumoricidal reactive oxygen intermediates. The end-result is eradication of residual tumor cells via neutrophil mediated antibody depen-dent cellular cytotoxicity (ADCC). The elimination of resid-ual tumor cells is thought to be essential in preventing relapse. Furthermore, the inflammatory response appears to confer a favorable cosmetic outcome via expedited healing and a rapid regeneration of the normal cutaneous architecture.
Clinical Use
Different sources of media describe the Clinical Use of 75567-37-2 differently. You can refer to the following data:
1. 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.
2. 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.
Dosage and Administration
Ingenol mebutate (chemical structure C25H34O6) has been formulated as a topical gel. Each gram contains 150 or 500 mcg of ingenol mebutate in a base of isopropyl alcohol, hydroxyethyl cellulose, citric acid monohydrate, sodium citrate, benzyl alcohol, and purified water.
For the indication of actinic keratoses. The 0.015 % gel is applied once daily for three consecutive days (face or scalp) while the 0.05 % gel is applied once daily for two consecu-tive days (trunk or extremities).
side effects
The most common side effects of ingenol mebutate were application-site reactions including erythema, scale, crust-ing, edema, vesiculation, erosions, ulceration, pruritus, pain, and irritation. Skin reactions typically occurred within 1 day of treatment initiation, peaking in intensity 1 week following application, and resolving within 2 weeks on the face/scalp and 4 weeks on the trunk/extremities.
Reports of periocular pain, edema, ptosis have been docu-mented. Prompt hand washing after application and avoid-ance of contact with the eyes is recommended.
No evidence of skin sensitization, photoirritation, or pho-toallergic potential has been demonstrated.
Ingenol mebutate is pregnancy category C. It is unknown if ingenol mebutate is secreted in the breast milk of lactating women.
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.
Originator
Peplin (United States)
Uses
Different sources of media describe the Uses of 75567-37-2 differently. You can refer to the following data:
1. 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.
2. Ingenol 3-Angelate is known to exhibit antitumor activities which induces plasma membrane and mitochondrial disruption and necrotic cell death.
Definition
ChEBI: A tetracyclic diterpenoid ester obtained by formal condensation of the carboxy group of (2Z)-2-methylbut-2-enoic (angelic) acid with the 3-hydroxy group of ingenol. Used for the topical treatment of actinic keratosis.
Brand name
Picato
Biochem/physiol Actions
Ingenol-3-angelate, is a phorbol ester-like compound or a diacylglycerol analog that is used in the treatment of several disorders like skin cancer. It is also known as PEP005. Ingenol-3-angelate stimulates the initiation of the enzyme by providing PKCs (protein kinase C) to cellular membranes.
Synthesis
Although
several synthetic approaches to the ingenol family of terpenes have been reported,97-113 Liang and
coworkers at LEO Pharma have reported a semisynthesis of the API from naturally-occurring ingenol.
This natural product’s accessibility from the seeds of E. lathyris renders it widely commercial on scale.
The conversion of ingenol to ingenol mebutate involves a protection, esterification, and deprotection
strategy to procure scale quantities of the drug.114 Conversion of ingenol (87) to the
corresponding 5,20-acetonide 88 proceeded in good yield using a protocol modified from the original
conditions described by Hecker. A considerable amount of study was conducted by Liang to affect
efficient angeloylation with minimal isomerization of the double-bond to the corresponding Z-isomer
(tiglate). It was found that angelic anhydride 89 (which is a commercially available reagent, but for
process scale was prepared immediately prior to usage from the self-condensation of 99.5% pure angelic
acid with 0.5 equivalents of DCC) in the presence of LHMDS gave acetonide 90 in over 95%
conversion and was practically free of the undesired tiglate bi-product after recrystallization (73%
yield).96 Deprotection of the acetonide 90 was affected using phosphoric acid and after three
recrystallizations, ingenol mebutate (XIV) was produced on multigram scale in a combined yield of
37% starting from ingenol 87.
Check Digit Verification of cas no
The CAS Registry Mumber 75567-37-2 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 7,5,5,6 and 7 respectively; the second part has 2 digits, 3 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 75567-37:
(7*7)+(6*5)+(5*5)+(4*6)+(3*7)+(2*3)+(1*7)=162
162 % 10 = 2
So 75567-37-2 is a valid CAS Registry Number.
75567-37-2Relevant articles and documents
Identification, structural modification, and dichotomous effects on human immunodeficiency virus type 1 (HIV-1) replication of ingenane esters from Euphorbia kansui
Liu, Qingbo,Li, Wei,Huang, Li,Asada, Yoshihisa,Morris-Natschke, Susan L.,Chen, Chin-Ho,Lee, Kuo-Hsiung,Koike, Kazuo
, p. 618 - 627 (2018/07/29)
Euphorbia kansui showed potent anti-HIV-1 activity during screening of a library composed of plant extracts from Euphorbiaceae and Thymelaeaceae families. Bioassay-guided isolation led to identification of ingenane esters as the active compounds. Further chemical modification resulted in 3-(2-naphthoyl)ingenol (23), which exhibited the most potent anti-HIV-1 activity. Compound 23 also acted as an HIV-1-latency-reversing agent on activation of HIV-1 replication in a latently infected U1 cell model and a T cell latent HIV-1 model JLat-A2.
A CONTINUOUS FLOW PROCESS FOR THE PREPARATION OF INGENOL-3-MEBUTATE
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Paragraph 0072-0077, (2015/12/08)
Disclosed is a continuous process for the preparation of ingenol-3-mebutate by reaction, in solution, of ingenol or ingenol anion and angelic anhydride or an equivalent angelylating agent. The continuous flow process is preferably performed in the presence of a base such as lithium hexamethyl disilazane (LiHMDS) and/or an activating agent such as dicyclohexylcarbodiimide (DCC). Also disclosed is a process for recycling the other reaction products obtained in the continuous process for preparation of ingenol-3-mebutate for formation of ingenol, which can then be recycled to form ingenol-3-mebutate.
PROCESS FOR THE PREPARATION OF INGENOL-3-ANGELATE FROM 20-DEOXY-INGENOL
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Page/Page column 4; 5; 7, (2014/02/15)
The present invention provides a method for preparing ingenol-3-angelate.
