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.
Chemical Properties
White powder, soluble in organic solvents such as methanol, ethanol, and DMSO, derived from the whole herb of the Euphorbia family.
Originator
Peplin (United States)
Uses
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.
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?ˉs 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.
target
gp120/CD4 | HIV | PKC | P-gp | NF-kB | ERK
References
References/Citations
