30220-46-3 Usage
Description
Different sources of media describe the Description of 30220-46-3 differently. You can refer to the following data:
1. Ingenol is a diterpenoid related to phorbol, derived from the milkweed plant E. peplus.1 It is a protein kinase C activator that displays a Ki value of 30 μM and an ED50 value of 27 μM in vitro. Most ingenol esters are tumor-promoting. However, ingenol mebutate possesses anti-tumor activity when used topically for actinic keratosis.
2. Ingenol is a diterpenoid related to phorbol, derived from the milkweed plant E. peplus. It is a protein kinase C activator that displays a Ki value of 30 μM and an ED50 value of 27 μM in vitro. Most ingenol esters are tumor-promoting. However, ingenol mebutate possesses anti-tumor activity when used topically for actinic keratosis.
Chemical Properties
Isolated in 1968, ingenol, a highly oxygenated tetracyclic diterpene classified as a member of the phorboid family, is the parent compound of several dozen naturally occurring ingenanes that possess the same carbon skeleton but varied peripheral functionalities. In addition to their intriguing “inside-outside” bridged BC ring system, the ingenanes display interesting biological profiles that range from tumorpromoting to anti-leukemic and anti-HIV activities. Since the early 1980s, this combination of important biological function and complex architecture has inspired the efforts of numerous synthetic chemists.4 Previously, we reported an approach toward 1 wherein known a-ketoester 2 was advanced to diene 3, which served as a ring-closing metathesis substrate in a first generation Grubbs reaction that delivers the ingenane tetracycle 4.
Ingenol mebutate
Ingenol mebutate is a selective small-molecule activator of protein kinase C (PKC) isolated from the plant Euphorbia peplus with potential antineoplastic activity. Ingenol mebutate activates various protein kinase C (PKC) isoforms, thereby inducing apoptosis in some tumor cells, including myeloid leukemia cells, melanoma cells, and basal cell carcinoma cells. The PKC family consists of signaling isoenzymes that regulate many cell processes including proliferation, differentiation, and apoptosis.
Ingenol mebutate was approved by the FDA in January 2012, and it is marketed under the name Picato?. Picato gel is indicated for the topical treatment of actinic keratosis. Before approval, ingenol mebutate was called PEP005 as an investigational drug. PEP005 is a selective small molecule activator of protein kinase C (PKC) extracted from the plant Euphorbia peplus, whose sap has been used as a traditional medicine for the treatment of skin conditions including warts and cancer. PEP005 also has potent anti-leukemic effects, inducing apoptosis in myeloid leukemia cell lines and primary AML cells at nanomolar concentrations.
Ingenol mebutate gel (Picato) is a topical cream that the manufacturer is requesting to use as a secondline treatment in patients with actinic keratosis (AK) who have failed or are intolerant to 5-fluorouracil (5-FU). Ingenol mebutate gel is available in two strengths – a 0.015% dose for lesions on the face and scalp and a 0.05% dose for lesions on the trunk and extremities.
Pharmacokinetics & metabolism
The pharmacokinetics investigation of the systemic absorption of ingenol mebutate gel 0.05% was evaluated in a randomized vehicle-controlled double blind study, in which 1 g was applied to a contiguous 100 cm2 area of multiple AKs on the dorsal forearms of 16 patients in two consecutive daily applications. This clinical trial showed that there was no detectable systemic absorption of the parent drug or its two principal metabolites (both acyl isomers of ingenol mebutate), when the limit of detection was 0.1 ng/ml.
In vitro studies using [3H]-ingenol mebutate showed that metabolism of the drug by human hepatocytes is extensive. Other in vitro studies showed that ingenol mebutate neither induces human CYPP450 enzymes CYP1A2, 2C9 and 3A4a, nor inhibits CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4.
Uses
Ingenol, is the analogue of Ingenol 3-Angelate (I655800), which has anti-tumor activity when used topically for the treatment of actinic keratosis.
Definition
ChEBI: A tetracyclic diterpenoid that is 1a,2,5,5a,6,9,10,10a-octahydro-1H-2,8a-methanocyclopenta[a]cyclopropa[e][10]annulen-11-one substituted at positions 5, 5a and 6 by hydroxy groups, positions 1, 1, 7 and 9 by met
yl groups, position 4 by a hydroxymethyl group and position 1 by an oxo group (the 1aR,2S,5R,5aR,6S,8aS,9R,10aR diastere
mer).
Check Digit Verification of cas no
The CAS Registry Mumber 30220-46-3 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 3,0,2,2 and 0 respectively; the second part has 2 digits, 4 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 30220-46:
(7*3)+(6*0)+(5*2)+(4*2)+(3*0)+(2*4)+(1*6)=53
53 % 10 = 3
So 30220-46-3 is a valid CAS Registry Number.
InChI:InChI=1/C20H28O5/c1-9-7-19-10(2)5-13-14(18(13,3)4)12(17(19)24)6-11(8-21)16(23)20(19,25)15(9)22/h6-7,10,12-16,21-23,25H,5,8H2,1-4H3/t10-,12+,13-,14+,15+,16-,19+,20-/m1/s1
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.
Uemura,Hirata
, p. 3673 (1971)
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.
METHODS OF SYNTHESIS OF INGENOL AND INTERMEDIATES THEREOF
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Page/Page column 84, (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.
