Dasatinib
Descripción general
Descripción
Dasatinib es un medicamento de terapia dirigida que se utiliza principalmente para tratar ciertos casos de leucemia mieloide crónica y leucemia linfoblástica aguda. Es particularmente efectivo en casos que son positivos para el cromosoma Filadelfia. This compound es un inhibidor de la tirosina quinasa que funciona bloqueando una serie de tirosina quinasas, incluidas Bcr-Abl y la familia de la quinasa Src .
Aplicaciones Científicas De Investigación
Dasatinib tiene una amplia gama de aplicaciones de investigación científica:
Química: Se utiliza como un compuesto modelo en estudios que involucran inhibidores de la tirosina quinasa.
Biología: Investigado por sus efectos en varios procesos celulares, incluyendo el crecimiento celular y la apoptosis.
Medicina: Se utiliza principalmente en el tratamiento de la leucemia mieloide crónica y la leucemia linfoblástica aguda. .
Industria: Utilizado en el desarrollo de nuevos productos farmacéuticos y agentes terapéuticos
Mecanismo De Acción
Dasatinib ejerce sus efectos inhibiendo múltiples tirosina quinasas, incluidas Bcr-Abl y la familia de la quinasa Src. Se une a las conformaciones activa e inactiva del dominio quinasa ABL, evitando la fosforilación y activación de las vías de señalización descendentes. Esta inhibición conduce a la supresión de la proliferación celular y la inducción de la apoptosis en las células cancerosas .
Compuestos Similares:
Imatinib: Otro inhibidor de la tirosina quinasa utilizado para indicaciones similares.
Nilotinib: Similar a this compound pero tiene un perfil de unión diferente y se utiliza en casos donde this compound no es efectivo.
Bosutinib: Otro inhibidor de la tirosina quinasa con un espectro de actividad diferente.
Singularidad: this compound es único en su capacidad de inhibir un amplio espectro de quinasas, incluyendo las conformaciones activa e inactiva del dominio quinasa ABL. Esto lo hace efectivo en casos donde otros inhibidores, como imatinib, pueden fallar debido a la resistencia .
Análisis Bioquímico
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
This compound 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, this compound can inhibit STAT5 signaling, which downregulates B-cell leukemia (BCL-x) (BCL2L1), Myeloid Cell Leukemia sequence 1 (MCL1), and cyclin D1 .
Molecular Mechanism
This compound exerts its effects at the molecular level through several mechanisms. It inhibits the active and inactive conformations of the ABL kinase domain . Moreover, this compound 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 this compound change over time. For instance, following a single oral administration of this compound 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
This compound 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 this compound .
Transport and Distribution
This compound is transported and distributed within cells and tissues. The absorption of this compound is mainly a passive process, but it is a substrate of the efflux transporters ABCB1 and ABCG2 in leukemic cells . The efflux of this compound is also regulated by ABCC4 and ABCC6 transporters .
Subcellular Localization
The subcellular localization of this compound and its effects on activity or function are crucial. For instance, treatment with the Src family kinase inhibitor this compound resulted in reduced nuclear localization of YAP5SA, such that most cells had a comparable level of YAP5SA in both nucleus and cytoplasm .
Métodos De Preparación
Rutas Sintéticas y Condiciones de Reacción: La síntesis de dasatinib implica múltiples pasos. Uno de los pasos clave incluye la reacción del 3-oxopropionato de etilo con 2-cloro-6-metil anilina en condiciones alcalinas. Esto es seguido por la adición de un solvente que contiene bromuro de cobre disuelto, y luego se agrega tiourea para ciclizar el compuesto para formar 2-amino-N-(2-cloro-6-metilfenil)tiazol-5-formamida. El paso final implica la síntesis de this compound haciendo reaccionar 4,6-dicloro-2-metilpirimidina, N-hidroxietil piperazina y 2-amino-N-(2-cloro-6-metilfenil)tiazol-5-formamida bajo la acción de álcali y líquido iónico .
Métodos de Producción Industrial: La producción industrial de this compound típicamente involucra la síntesis a gran escala utilizando condiciones de reacción similares a las descritas anteriormente. El proceso está optimizado para el rendimiento y la pureza, asegurando que el producto final cumpla con los estándares farmacéuticos .
Análisis De Reacciones Químicas
Tipos de Reacciones: Dasatinib se somete a varias reacciones químicas, incluyendo reacciones de oxidación, reducción y sustitución.
Reactivos y Condiciones Comunes:
Oxidación: this compound puede oxidarse usando reactivos como peróxido de hidrógeno u otros agentes oxidantes.
Reducción: Las reacciones de reducción se pueden llevar a cabo usando agentes reductores como el borohidruro de sodio.
Sustitución: Las reacciones de sustitución a menudo involucran nucleófilos o electrófilos en condiciones apropiadas.
Productos Mayores: Los productos principales formados a partir de estas reacciones dependen de los reactivos y las condiciones específicas utilizadas. Por ejemplo, la oxidación puede conducir a la formación de this compound N-óxido, mientras que la reducción puede producir derivados reducidos de this compound .
Comparación Con Compuestos Similares
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 this compound is not effective.
Bosutinib: Another tyrosine kinase inhibitor with a different spectrum of activity.
Uniqueness: this compound 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 .
Propiedades
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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Feasible Synthetic Routes
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