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药品详细

Trabectedin(曲贝)

化学结构式图
中文名
曲贝
英文名
Trabectedin
分子式
C39H43N3O11S
化学名
(1R,2R,3R,11S,12S,14R,26R)-5,6',12-trihydroxy-6,7'-dimethoxy-7,21,30-trimethyl-27-oxo-3',4'-dihydro-2'H-17,19,28-trioxa-24-thia-13,30-diazaspiro[heptacyclo[12.9.6.1^{3,11}.0^{2,13}.0^{4,9}.0^{15,23}.0^{16,20}]triacontane-26,1'-isoquinoline]-4(9),5,7,15(23),16(20),21-hexaen-22-yl acetate
分子量
Average: 761.837
Monoisotopic: 761.261829923
CAS号
114899-77-3
ATC分类
L01C 植物碱和其他天然产物
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

Trabectedin, also referred as ET-743 during its development, is a marine derived antitumoral agent discovered in the Carribean tunicate Ecteinascidia turbinata and now produced synthetically. Trabectedin has a unique mechanism of action. It binds to the minor groove of DNA interfering with cell division and genetic transcription processes and DNA repair machinery. It is approved for use in Europe, Russia and South Korea for the treatment of advanced soft tissue sarcoma refractory to or unsuitable to receive anthracycline or ifosfamide chemotherapy.

生产厂家
    封装厂家
    参考
    Synthesis Reference Not Available
    General Reference
    1. Tavecchio M, Natoli C, Ubezio P, Erba E, D’Incalci M: Dynamics of cell cycle phase perturbations by trabectedin (ET-743) in nucleotide excision repair (NER)-deficient and NER-proficient cells, unravelled by a novel mathematical simulation approach. Cell Prolif. 2007 Dec;40(6):885-904. Pubmed
    2. Krasner CN, McMeekin DS, Chan S, Braly PS, Renshaw FG, Kaye S, Provencher DM, Campos S, Gore ME: A Phase II study of trabectedin single agent in patients with recurrent ovarian cancer previously treated with platinum-based regimens. Br J Cancer. 2007 Dec 17;97(12):1618-24. Epub 2007 Nov 13. Pubmed
    3. Carter NJ, Keam SJ: Trabectedin : a review of its use in the management of soft tissue sarcoma and ovarian cancer. Drugs. 2007;67(15):2257-76. Pubmed
    4. Trabectedin: Ecteinascidin 743, Ecteinascidin-743, ET 743, ET-743, NSC 684766. Drugs R D. 2006;7(5):317-28. Pubmed
    5. Zhou SF, Zhou ZW, Yang LP, Cai JP: Substrates, inducers, inhibitors and structure-activity relationships of human Cytochrome P450 2C9 and implications in drug development. Curr Med Chem. 2009;16(27):3480-675. Epub 2009 Sep 1. Pubmed
    剂型
    规格
    化合物类型
    Type small molecule
    Classes
    • Phenylacetates
    • Methoxyphenols
    • Phenylpropylamines
    • (Iso)quinolines and Derivatives
    • Amphetamines
    • Catecholamines and Derivatives
    Substructures
    • Carboxylic Acids and Derivatives
    • Ethers
    • Hydroxy Compounds
    • Acetates
    • Acetals and Derivatives
    • Aliphatic and Aryl Amines
    • Phenols and Derivatives
    • Lactones
    • Phenylacetates
    • Piperazines
    • Benzene and Derivatives
    • Aminals and Derivatives
    • Dioxoles
    • Hydroquinones
    • Methoxyphenols
    • Catechols
    • Phenethylamines
    • Heterocyclic compounds
    • Aromatic compounds
    • Benzodioxoles
    • Anisoles
    • Phenylpropylamines
    • (Iso)quinolines and Derivatives
    • Phenyl Esters
    • Amphetamines
    • Catecholamines and Derivatives
    适应症
    药理
    Indication Indicated for treatment of advanced soft tissue sarcoma in patients refractory to or unsuitable to receive anthracycline or ifosfamide chemotherapy in Europe, Russia and South Korea. Approved for orphan drug status by the U.S. FDA for treatment of soft tissue sarcomas and ovarian cancer. Investigated for use/treatment in cancer/tumors (unspecified), gastric cancer, ovarian cancer, pediatric indications, sarcoma, and solid tumors.
    Pharmacodynamics Two of the rings in the drug's structure allows it to covalently bind to the minor groove of DNA. The third ring protrudes from the DNA which lets it interact with nearby nuclear proteins. This has the additive effect of blocking cell division at the G2 phase.
    Mechanism of action Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G2 phase, while cells at the G1 phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications.
    Absorption Administered intravenously.
    Volume of distribution Not Available
    Protein binding 94 to 98%
    Metabolism
    Not Available
    Route of elimination Not Available
    Half life 33-50 hours
    Clearance Not Available
    Toxicity Not Available
    Affected organisms Not Available
    Pathways Not Available
    理化性质
    Properties
    State solid
    Experimental Properties Not Available
    Predicted Properties
    Property Value Source
    water solubility 3.28e-01 g/l ALOGPS
    logP 2.04 ALOGPS
    logP 3.99 ChemAxon
    logS -3.4 ALOGPS
    pKa (strongest acidic) 9.27 ChemAxon
    pKa (strongest basic) 7.66 ChemAxon
    physiological charge 1 ChemAxon
    hydrogen acceptor count 12 ChemAxon
    hydrogen donor count 4 ChemAxon
    polar surface area 168.72 ChemAxon
    rotatable bond count 4 ChemAxon
    refractivity 196.92 ChemAxon
    polarizability 77.09 ChemAxon
    药物相互作用
    食物相互作用
    Not Available

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