114899-77-3 Usage
Description
Ecteinascidin 743, also known as Trabectedin or Yondelis, is a tetrahydroisoquinoline alkaloid derived from the Caribbean tunicate Ecteinascidia turbinata. It is a potent marine natural product with significant antitumor activity, characterized by its unique mechanism of action that involves binding to DNA and disrupting the binding of transcription factors involved in cell proliferation.
Uses
Used in Anticancer Applications:
Ecteinascidin 743 is used as an antineoplastic agent for the treatment of soft tissue sarcoma (STS) and relapsed ovarian cancer. It is the first marine anticancer agent approved in the European Union for patients with STS, demonstrating its effectiveness against a range of solid tumor cell lines, human xenografts, and tumor explants. The drug has shown potencies ranging from 1 pM to 10 nM against various cancer types, including melanoma, non-small-cell lung, ovarian, renal, prostate, and breast cancer.
Used in Drug Development:
Ecteinascidin 743 serves as a valuable compound in the development of novel drug delivery systems and therapeutic strategies for cancer treatment. Its unique mechanism of action and potent antitumor activity make it an important candidate for further research and development in the pharmaceutical industry.
Originator
University of Illinois (US)
Clinical Use
Antineoplastic agent: Advanced soft tissue sarcoma Ovarian cancer
Side effects
The most common adverse events included nausea, fatigue, vomiting, anorexia, neutropenia, and increases in aspartate aminotransferase and alanine aminotransferase liver enzymes. To combat the nausea and vomiting, all patients must receive 20mg of dexamethasone intravenously before the trabectedin infusion. Not only does this pretreatment have an antiemetic effect, it also appears to offer a hepatoprotective benefit. Concomitant administration of potent inhibitors and inducers of CYP3A4 should be avoided since plasma levels of this CYP3A4- metabolized drug will be affected. Trabectedin is contraindicated in patients with a known hypersensitivity to trabectedin, concurrent serious or uncontrolled infection, or breast-feeding. Trabectedin should also not be administered in combination with yellow fever vaccine. Finally, there are strict criteria regarding absolute neutrophil count, platelet count, and renal and hepatic enzyme levels for permission to initiate or continue treatment with trabectedin.
Synthesis
While the challenging total synthesis of trabectedin has been accomplished by a few research groups, the commercial preparation begins from readily available cyanosafracin B in 21 steps. Following the Boc and MOM protection of the amine and phenol functionalities, respectively, the methoxy-pquinone was hydrolyzed with sodium hydroxide in methanol. The resulting quinine was reduced (hydrogen over Pd/C) to give an unstable hydroquinone that was subsequently alkylated with bromochloromethane and allyl bromide. The MOM and Boc groups were then removed followed by cleavage of the amide by Edman degradation (through formation of the thiourea with phenyl isothiocyanate and treatment with HCl in 1,4-dioxane). At this point, the amine was protected as the TROC carbamate before reprotecting the phenol as the MOM ether and then liberating the amine with zinc in acetic acid. The amine was converted to an alcohol moiety with sodium nitrite in acetic acid, and this handle was acylated with (S)-N-[(trichloroethoxy)carbonyl]-S-(9-fluorenylmethyl)cysteine. Removal of the allyl-protecting group followed by oxidation provided an 492 Shridhar Hegde and Michelle Schmidt alpha-hydroxy ketone intermediate. Dehydration and deprotection of the cysteine established the Michael addition of the thiol to the o-quinone methide with concomitant trapping with acetic anhydride. The remaining steps involved removal of protecting groups, installation of the tetrahydroisoquinoline ring via a Pictet Spengler reaction, and conversion of the cyano to the alcohol of the carbinolamine with silver nitrate in acetonitrile and water.
Drug interactions
Potentially hazardous interactions with other drugs
Alcohol: Avoid concomitant use.
Antibacterials: concentration reduced by rifampicin.
Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Vaccines: risk of generalised infections - avoid.
Metabolism
Metabolised in the liver, mainly by cytochrome P450 isoenzyme CYP3A4. Excreted mainly via the faeces.
Check Digit Verification of cas no
The CAS Registry Mumber 114899-77-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,1,4,8,9 and 9 respectively; the second part has 2 digits, 7 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 114899-77:
(8*1)+(7*1)+(6*4)+(5*8)+(4*9)+(3*9)+(2*7)+(1*7)=163
163 % 10 = 3
So 114899-77-3 is a valid CAS Registry Number.
114899-77-3Relevant articles and documents
A Concise and Practical Semisynthesis of Ecteinascidin 743 and (–)-Jorumycin
Xu, Shanghu,Wang, Guan,Zhu, Jinjin,Shen, Chuang,Yang, Zhezhou,Yu, Jun,Li, Zhong,Lin, Tanghuan,Sun, Xun,Zhang, Fuli
, p. 975 - 983 (2017)
Ecteinascidin 743 is an antitumor drug used to treat specific soft-tissue sarcomas (STS). In this paper, we present a concise and practical semisynthesis of ecteinascidin 743 starting from safracin B. The strategy involves the direct conversion of an aliphatic amino group into an acetoxy group. By this approach, ecteinascidin 743 was synthesized in 14 steps and 1.5 % overall yield. The synthetic approach also provided access to other tetrahydroisoquinoline alkaloids, such as (–)-jorumycin (a promising anticancer candidate). (–)-Jorumycin was prepared in six steps and 24.1 % overall yield from safracin B.
A Scalable Total Synthesis of the Antitumor Agents Et-743 and Lurbinectedin
He, Weiming,Zhang, Zhigao,Ma, Dawei
, p. 3972 - 3975 (2019)
An efficient and scalable approach is described for the total synthesis of the marine natural product Et-743 and its derivative lubinectedin, which are valuable antitumor compounds. The method delivers 1.6 % overall yield in 26 total steps from Cbz-protected (S)-tyrosine. It features the use of a common advanced intermediate to create the right and left parts of these compounds, and a light-mediated remote C?H bond activation to assemble a benzo[1,3]dioxole-containing intermediate.
IMPROVED PROCESS FOR THE PREPARATON OF PURE (1'R,6R,6aR,7R,13S,14S,16R)-5-(ACETYLOXY)-3',4',6,6a,7,13,14,16-OCTAHYDRO-6',8,14-TRIHYDROXY-7',9-DIMETHOXY-4,10,23-TRIMETHYLSPIRO[6,16-(EPITHIOPROPANOXYMETH ANO)-7,13-IMINO-12H-1,3-DIOXOLO[7,8]ISOQUINO[3,2-b][3]BENZAZOCINE-20,1'(2'H)-ISOQUINOLIN]-19-ONE POLYMORPH THERE OF
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Page/Page column 16; 21-22; 23, (2021/01/23)
The present invention provides pure (1'R,6R,6aR,7R,13S,14S,16R)-5-(acetyloxy)-3',4',6,6a,7,13,14,16-octahydro-6',8,14-trihydroxy-7',9-dimethoxy-4,10,23-trimethyl spiro[6,16-(epithiopropanoxymethano)-7,13-imino-12H-1,3-dioxolo[7,8]isoquino [3,2-b][3] benzazocine-20,1'(2'H)-isoquinolin]-19-one of formula (1) substantially free from one or more impurities selected from intermediate compound of formula (50), cyclic impurity of formula (A), deshydroxy impurity of formula (B) and hydroxy impurity of formula (C).
Preparation of natural product Trabectedin
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, (2019/07/04)
The invention provides a preparation method of a natural product Trabectedin, particularly an Et-743 preparation method, wherein tyrosine is used as a starting substrate, synthesis can be completed through a 26-step reaction, the raw materials and the reagents used in the synthetic route are relatively easy to obtain, the reaction conditions are relatively mild, and the method is suitable for large-scale preparation.
