30220-46-3Relevant articles and documents
Toxicity Reduction of Euphorbia kansui Stir-Fried with Vinegar Based on Conversion of 3-O-(20E,40Z-Decadi-enoyl)-20-O-acetylingenol
Zhang, Qiao,Zhang, Yi,Zhou, Shi-Kang,Wang, Kan,Zhang, Min,Chen, Pei-Dong,Yao, Wei-Feng,Tang, Yu-Ping,Wu, Jian-Hua,Zhang, Li
, (2019)
The dried roots of Euphorbia kansui S.L.Liou ex S.B.Ho have long been used to treat edema in China. However, the severe toxicity caused by Euphorbia kansui (EK) has seriously restricted its clinical application. Although EK was processed with vinegar to reduce its toxicity, the detailed mechanisms of attenuation in toxicity of EK stir-fried with vinegar (VEK) have not been well delineated. Diterpenoids are the main toxic ingredients of EK, and changes in these after processing may be the underlying mechanism of toxicity attenuation of VEK. 3-O-(20E,40Z-decadienoyl)-20-O-acetylingenol (3-O-EZ) is one of the diterpenoids derived from EK, and the content of 3-O-EZ was significantly reduced after processing. This study aims to explore the underlying mechanisms of toxicity reduction of VEK based on the change of 3-O-EZ after processing with vinegar. Based on the chemical structure of 3-O-EZ and the method of processing with vinegar, simulation experiments were carried out to confirm the presence of the product both in EK and VEK and to enrich the product. Then, the difference of peak area of 3-O-EZ and its hydrolysate in EK and VEK were detected by ultra-high-performance liquid chromatography (UPLC). Furthermore, the toxicity effect of 3-O-EZ and its hydrolysate, as well as the underlying mechanism, on zebrafish embryos were investigated. The findings showed that the diterpenoids (3-O-EZ) in EK can convert into less toxic ingenol in VEK after processing with vinegar; meanwhile, the content of ingenol in VEK was higher than that of EK. More interestingly, the ingenol exhibited less toxicity (acute toxicity, developmental toxicity and organic toxicity) than that of 3-O-EZ, and 3-O-EZ could increase malondialdehyde (MDA) content and reduce glutathione (GSH) content; cause embryo oxidative damage by inhibition of the succinate dehydrogenase (SDH) and superoxide dismutase (SOD) activity; and induce inflammation and apoptosis by elevation of IL-2 and IL-8 contents and activation of the caspase-3 and caspase-9 activity. Thus, this study contributes to our understanding of the mechanism of attenuation in toxicity of VEK, and provides the possibility of safe and rational use of EK in clinics.
Development of a concise synthesis of (+)-ingenol
McKerrall, Steven J.,J?rgensen, Lars,Kuttruff, Christian A.,Ungeheuer, Felix,Baran, Phil S.
, p. 5799 - 5810 (2014)
The complex diterpenoid (+)-ingenol possesses a uniquely challenging scaffold and constitutes the core of a recently approved anti-cancer drug. This full account details the development of a short synthesis of 1 that takes place in two separate phases (cyclase and oxidase) as loosely modeled after terpene biosynthesis. Initial model studies establishing the viability of a Pauson-Khand approach to building up the carbon framework are recounted. Extensive studies that led to the development of a 7-step cyclase phase to transform (+)-3-carene into a suitable tigliane-type core are also presented. A variety of competitive pinacol rearrangements and cyclization reactions were overcome to develop a 7-step oxidase phase producing (+)-ingenol. The pivotal pinacol rearrangement is further examined through DFT calculations, and implications for the biosynthesis of (+)-ingenol are discussed.
A convenient method for the preparation of 20-[18O]-labeled ingenol
Pospí?il, Ji?í,Béres, Tibor,Strnad, Miroslav
, p. 1421 - 1424 (2017)
A short and efficient protecting group-free synthesis of isotopically labeled 20-[18O]-ingenol has been developed. Based on a highly selective (only one out of four hydroxy groups) Mitsunobu reaction of ingenol with 18O2-acetic acid and subsequent methanolysis, this route yielded the desired 20-[18O]-ingenol in high yield and chemical and isotopic purity.
14-Step synthesis of (+)-ingenol from (+)-3-carene
Jorgensen, Lars,McKerrall, Steven J.,Kuttruff, Christian A.,Ungeheuer, Felix,Felding, Jakob,Baran, Phil S.
, p. 878 - 882 (2013)
Ingenol is a diterpenoid with unique architecture and has derivatives possessing important anticancer activity, including the recently Food and Drug Administration-approved Picato, a first-in-class drug for the treatment of the precancerous skin condition actinic keratosis. Currently, that compound is sourced inefficiently from Euphorbia peplus. Here, we detail an efficient, highly stereocontrolled synthesis of (+)-ingenol proceeding in only 14 steps from inexpensive (+)-3-carene and using a two-phase design. This synthesis will allow for the creation of fully synthetic analogs of bioactive ingenanes to address pharmacological limitations and provides a strategic blueprint for chemical production. These results validate two-phase terpene total synthesis as not only an academic curiosity but also a viable alternative to isolation or bioengineering for the efficient preparation of polyoxygenated terpenoids at the limits of chemical complexity.
A CONTINUOUS FLOW PROCESS FOR THE PREPARATION OF INGENOL-3-MEBUTATE
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Paragraph 0088-0091, (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.
METHODS OF SYNTHESIS OF INGENOL AND INTERMEDIATES THEREOF
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, (2014/12/12)
The present invention relates generally to methods of synthesis of diterpene heterocylic compounds. More particularly, the present invention relates to efficient methods of synthesis of ingenol (Formula (21), CAS 30220-46-3), from a compound of formula (1). The present invention also provides for various advantageous intermediates along the synthetic route of ingenol. Efficient synthesis of ingenol is important in the design and synthesis of related analogues, such as ingenol-3-angelate.
Total synthesis of ingenol
Nickel, Andrew,Maruyama, Toru,Tang, Haifeng,Murphy, Prescott D.,Greene, Blake,Yusuff, Naeem,Wood, John L.
, p. 16300 - 16301 (2007/10/03)
A total synthesis of the biologically important diterpene ingenol has been completed. Ring-closing olefin metathesis was used to construct the strained "inside-outside" tetracyclic skeleton, and a series of diastereoselective reactions were employed to complete the synthesis. Another naturally occurring ingenane, 20-deoxyingenol, has also been prepared. Copyright
On the Chemistry of Ingenol, III. Synthesis of 3-Deoxy-3-oxoingenol, Some 5-Esters and of Ethers and Acetals of Ingenol
Sorg, Bernd,Hecker, Erich
, p. 1640 - 1647 (2007/10/02)
3-Deoxy-3-oxoingenol (3) was prepared from ingenol-5,20-acetonide (25) by oxidation and subsequent removal of the acetonide. 3 was acylated to give homologous 5,20-diacylates 5-9.From these the 5-monoacylates 14, 15 and 17 were obtained in only moderate yields.Therefore the 20-silyl ether 10 (prepared from 3) was acylated.After smooth removal of the silyl ether the homologous 5-acylates 16, 18 and 19 resulted in good yield.The 5,20-dibutyrate 6 and all 5-acylates prepared (14-19) showed no irritant activity on the mouse ear.The 3-oxo-5-acylates 14-19 could not be reduced to give ingenol-5-acylates (24).Therefore various ingenol derivatives, 29-32, with suitable protected hydroxyl functions as well as the corresponding 5-decanoates 35-38 were synthesized.The protecting groups of the derivatives 35-38 could however not be cleaved off to yield ingenol-5-decanoate (24). - Key words: Cocarcinogen, Diterpenes, Ingenol Esters, Tumor Promoter
On the Chemistry of Ingenol, I. Ingenol and Some of its Derivatives
Opferkuch, H. J.,Adolf, W.,Sorg, B.,Kusumoto, S.,Hecker, E.
, p. 878 - 887 (2007/10/02)
The tetracyclic polyfunctional diterpene ingenol (1) is the prototype of many diterpenoid parent alcohols of the ingenane type.Esters of these parent alcohols occur-partly together with esters of polyfunctional diterpene parent alcohols of the tigliane and daphnane type - as irritant, cocarcinogenic and antineoplastic principles in spesies of the family Euphorbiaceae (Spurge).Preparation of 1 from latex of Euphorbia ingens E.May as well as of some functional derivatives of 1 are described. - Key words: Cocarcinogens, Diterpene Esters, Euphorbiaceae, Tumor Promoters
