ダサチニブ
概要
説明
ダサチニブは、主に慢性骨髄性白血病や急性リンパ性白血病の特定の症例を治療するために使用される標的療法薬です。特にフィラデルフィア染色体陽性の症例に有効です。 ダサチニブは、Bcr-AblやSrcキナーゼファミリーなど、複数のチロシンキナーゼを阻害するチロシンキナーゼ阻害剤です .
2. 製法
合成ルートと反応条件： ダサチニブの合成は、複数の工程を伴います。主要な工程の1つは、アルカリ条件下でエチル3-オキソプロピオネートと2-クロロ-6-メチルアニリンを反応させることです。次に、溶解した臭化銅を含む溶媒を添加し、その後チオ尿素を添加して化合物を環化させ、2-アミノ-N-(2-クロロ-6-メチルフェニル)チアゾール-5-ホルムアミドを生成します。 最後の工程では、4,6-ジクロロ-2-メチルピリミジン、N-ヒドロキシエチルピペラジン、および2-アミノ-N-(2-クロロ-6-メチルフェニル)チアゾール-5-ホルムアミドをアルカリとイオン液の存在下で反応させることで、ダサチニブを合成します .
工業的生産方法： ダサチニブの工業的生産は、通常、上記と同様の反応条件を用いた大規模合成を行います。 このプロセスは収率と純度が最適化されており、最終製品が医薬品の規格を満たすことが保証されています .
科学的研究の応用
Dasatinib has a wide range of scientific research applications:
Chemistry: Used as a model compound in studies involving tyrosine kinase inhibitors.
Biology: Investigated for its effects on various cellular processes, including cell growth and apoptosis.
Medicine: Primarily used in the treatment of chronic myelogenous leukemia and acute lymphoblastic leukemia. .
Industry: Utilized in the development of new pharmaceuticals and therapeutic agents
作用機序
ダサチニブは、Bcr-AblやSrcキナーゼファミリーなど、複数のチロシンキナーゼを阻害することで効果を発揮します。ABLキナーゼドメインの活性型と不活性型の両方に結合し、下流のシグナル伝達経路のリン酸化と活性化を阻害します。 この阻害は、癌細胞の増殖抑制とアポトーシス誘導につながります .
類似化合物:
イマチニブ： 同じような適応症に使用される別のチロシンキナーゼ阻害剤です。
ニロチニブ： ダサチニブに似ていますが、結合プロファイルが異なり、ダサチニブが効果を発揮しない場合に使用されます。
ボスチニブ： 活性スペクトルが異なる別のチロシンキナーゼ阻害剤です。
ユニークさ： ダサチニブは、ABLキナーゼドメインの活性型と不活性型の両方を阻害する、幅広いキナーゼを阻害する能力においてユニークです。 これは、イマチニブなどの他の阻害剤が耐性により効果を発揮できない場合に有効です .
生化学分析
Biochemical Properties
Dasatinib plays a significant role in biochemical reactions by interacting with various enzymes, proteins, and other biomolecules. It primarily targets the ABL tyrosine kinase and the breakpoint cluster region (BCR) gene, which transcribe the chimeric protein BCR-ABL . This protein is associated with the uncontrolled activity of the ABL tyrosine kinase and is involved in the pathogenesis of chronic myeloid leukemia and 15-30% of acute lymphoblastic leukemia cases .
Cellular Effects
Dasatinib has profound effects on various types of cells and cellular processes. It influences cell function by impacting cell signaling pathways, gene expression, and cellular metabolism . For instance, dasatinib can inhibit STAT5 signaling, which downregulates B-cell leukemia (BCL-x) (BCL2L1), Myeloid Cell Leukemia sequence 1 (MCL1), and cyclin D1 .
Molecular Mechanism
Dasatinib exerts its effects at the molecular level through several mechanisms. It inhibits the active and inactive conformations of the ABL kinase domain . Moreover, dasatinib does not interact with some of the residues involved in mutations that may lead to relapse during imatinib treatment, making it a therapeutic alternative for patients with cancers that have developed imatinib-resistance .
Temporal Effects in Laboratory Settings
In laboratory settings, the effects of dasatinib change over time. For instance, following a single oral administration of dasatinib at a preclinical efficacious dose, tumoral phospho-BCR-ABL/phospho-CrkL were maximally inhibited at about 3 hours and recovered to basal levels by 24 hours .
Dosage Effects in Animal Models
Metabolic Pathways
Dasatinib is involved in several metabolic pathways. It is primarily metabolized by the CYP3A4 isoform of CYP450 . Additionally, flavin-containing monooxygenase 3 (FMO3), and uridine 5’-diphospho-glucuronosyltransferase (UGT) also metabolize dasatinib .
Transport and Distribution
Dasatinib is transported and distributed within cells and tissues. The absorption of dasatinib is mainly a passive process, but it is a substrate of the efflux transporters ABCB1 and ABCG2 in leukemic cells . The efflux of dasatinib is also regulated by ABCC4 and ABCC6 transporters .
Subcellular Localization
The subcellular localization of dasatinib and its effects on activity or function are crucial. For instance, treatment with the Src family kinase inhibitor Dasatinib resulted in reduced nuclear localization of YAP5SA, such that most cells had a comparable level of YAP5SA in both nucleus and cytoplasm .
準備方法
Synthetic Routes and Reaction Conditions: The synthesis of dasatinib involves multiple steps. One of the key steps includes the reaction of ethyl 3-oxopropionate with 2-chloro-6-methylaniline under alkaline conditions. This is followed by the addition of a solvent containing dissolved copper bromide, and then thiourea is added to cyclize the compound to form 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-formamide. The final step involves synthesizing dasatinib by reacting 4,6-dichloro-2-methylpyrimidine, N-hydroxyethyl piperazine, and 2-amino-N-(2-chloro-6-methylphenyl)thiazole-5-formamide under the action of alkali and ionic liquid .
Industrial Production Methods: Industrial production of dasatinib typically involves large-scale synthesis using similar reaction conditions as described above. The process is optimized for yield and purity, ensuring that the final product meets pharmaceutical standards .
化学反応の分析
反応の種類： ダサチニブは、酸化、還元、置換反応などのさまざまな化学反応を起こします。
一般的な試薬と条件:
酸化： ダサチニブは、過酸化水素などの酸化剤を使用して酸化することができます。
還元： 還元反応は、水素化ホウ素ナトリウムなどの還元剤を用いて行うことができます。
置換： 置換反応は、適切な条件下で求核剤または求電子剤を伴うことが多いです。
主要な生成物： これらの反応から生成される主要な生成物は、使用される特定の試薬と条件によって異なります。 たとえば、酸化によりダサチニブN-オキシドが生成され、還元によりダサチニブの還元誘導体が生成される可能性があります .
4. 科学研究への応用
ダサチニブは、科学研究で幅広く利用されています:
類似化合物との比較
Imatinib: Another tyrosine kinase inhibitor used for similar indications.
Nilotinib: Similar to dasatinib but has a different binding profile and is used in cases where dasatinib is not effective.
Bosutinib: Another tyrosine kinase inhibitor with a different spectrum of activity.
Uniqueness: Dasatinib is unique in its ability to inhibit a broad spectrum of kinases, including both active and inactive conformations of the ABL kinase domain. This makes it effective in cases where other inhibitors, such as imatinib, may fail due to resistance .
特性
IUPAC Name |
N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-1,3-thiazole-5-carboxamide |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C22H26ClN7O2S/c1-14-4-3-5-16(23)20(14)28-21(32)17-13-24-22(33-17)27-18-12-19(26-15(2)25-18)30-8-6-29(7-9-30)10-11-31/h3-5,12-13,31H,6-11H2,1-2H3,(H,28,32)(H,24,25,26,27) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
ZBNZXTGUTAYRHI-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CC1=C(C(=CC=C1)Cl)NC(=O)C2=CN=C(S2)NC3=CC(=NC(=N3)C)N4CCN(CC4)CCO |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C22H26ClN7O2S |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID4040979 |
Source
|
| Record name | Dasatinib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID4040979 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
488.0 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Solid |
Source
|
| Record name | Dasatinib | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015384 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Solubility |
1.28e-02 g/L |
Source
|
| Record name | Dasatinib | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015384 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Mechanism of Action |
Dasatinib, at nanomolar concentrations, inhibits the following kinases: BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. Based on modeling studies, dasatinib is predicted to bind to multiple conformations of the ABL kinase. In vitro, dasatinib was active in leukemic cell lines representing variants of imatinib mesylate sensitive and resistant disease. Dasatinib inhibited the growth of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL. Under the conditions of the assays, dasatinib was able to overcome imatinib resistance resulting from BCR-ABL kinase domain mutations, activation of alternate signaling pathways involving the SRC family kinases (LYN, HCK), and multi-drug resistance gene overexpression. |
Source
|
| Record name | Dasatinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01254 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
CAS No. |
302962-49-8, 863127-77-9 |
Source
|
| Record name | Dasatinib | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=302962-49-8 | |
| Description | CAS Common Chemistry is an open community resource for accessing chemical information. Nearly 500,000 chemical substances from CAS REGISTRY cover areas of community interest, including common and frequently regulated chemicals, and those relevant to high school and undergraduate chemistry classes. This chemical information, curated by our expert scientists, is provided in alignment with our mission as a division of the American Chemical Society. | |
| Explanation | The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated. | |
| Record name | Dasatinib [USAN:INN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0302962498 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
| Record name | Dasatinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01254 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Dasatinib | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=759877 | |
| Description | The NCI Development Therapeutics Program (DTP) provides services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new cancer therapeutic agents. | |
| Explanation | Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source. | |
| Record name | Dasatinib | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID4040979 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | N-(2-chloro-6-methylphenyl)-2-({6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl}amino)-1,3-thiazole-5-carboxamide | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.228.321 | |
| Description | The European Chemicals Agency (ECHA) is an agency of the European Union which is the driving force among regulatory authorities in implementing the EU's groundbreaking chemicals legislation for the benefit of human health and the environment as well as for innovation and competitiveness. | |
| Explanation | Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page. | |
| Record name | DASATINIB ANHYDROUS | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/X78UG0A0RN | |
| Description | The FDA Global Substance Registration System (GSRS) enables the efficient and accurate exchange of information on what substances are in regulated products. Instead of relying on names, which vary across regulatory domains, countries, and regions, the GSRS knowledge base makes it possible for substances to be defined by standardized, scientific descriptions. | |
| Explanation | Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required. | |
| Record name | Dasatinib | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015384 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
Melting Point |
280-286 °C, 280 - 286 °C |
Source
|
| Record name | Dasatinib | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01254 | |
| Description | The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug (i.e. chemical, pharmacological and pharmaceutical) data with comprehensive drug target (i.e. sequence, structure, and pathway) information. | |
| Explanation | Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode) | |
| Record name | Dasatinib | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015384 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
| Explanation | HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications. | |
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Retrosynthesis Analysis
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Strategy Settings
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| Min. plausibility | 0.01 |
| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
| Top-N result to add to graph | 6 |
Feasible Synthetic Routes
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