Bendamustine
Overview
Description
Bendamustine is a chemotherapy medication primarily used in the treatment of chronic lymphocytic leukemia, multiple myeloma, and non-Hodgkin’s lymphoma . It belongs to the class of alkylating agents and works by interfering with the function of DNA and RNA, leading to cell death . This compound was first synthesized in the early 1960s in the German Democratic Republic and was approved for medical use in the United States in 2008 .
Preparation Methods
Synthetic Routes and Reaction Conditions: Bendamustine hydrochloride can be synthesized through a multi-step process. The key intermediate, 1-methyl-5-[bis(2-chloroethyl)amino]-1H-benzimidazol-2-yl]lithium butanoate, is prepared and then converted to this compound hydrochloride . The process involves the use of various reagents and solvents, including trifluoroacetic acid and acetonitrile .
Industrial Production Methods: The industrial production of this compound hydrochloride aims for high purity (≥99%) and involves steps such as high-performance liquid chromatography (HPLC) for purification . The process is designed to be economical and environmentally friendly, avoiding the use of hazardous chemicals .
Chemical Reactions Analysis
Types of Reactions: Bendamustine undergoes several types of chemical reactions, including alkylation, hydrolysis, and oxidation . As an alkylating agent, it forms intra- and inter-strand crosslinks between DNA bases, leading to cell death .
Common Reagents and Conditions:
Alkylation: this compound forms electrophilic alkyl groups that covalently bond to DNA bases.
Hydrolysis: The compound is hydrolyzed to inactive metabolites in the liver.
Major Products: The major products formed from these reactions include the inactive metabolites and the crosslinked DNA .
Scientific Research Applications
Bendamustine has a wide range of scientific research applications:
Chemistry: It is studied for its unique bifunctional properties, combining alkylating and antimetabolite activities.
Biology: Research focuses on its effects on DNA and RNA, as well as its immunomodulatory properties.
Industry: It is used in the development of new chemotherapy regimens and combination therapies.
Mechanism of Action
Bendamustine exerts its effects through multiple mechanisms:
Alkylation: It forms intra- and inter-strand crosslinks between DNA bases, leading to cell death.
Activation of DNA-Damage Responses: this compound activates DNA-damage stress responses and apoptosis.
Inhibition of Mitotic Checkpoints: It inhibits mitotic checkpoints and induces mitotic catastrophe.
Molecular Targets: The primary targets are the DNA bases, leading to the disruption of DNA replication and transcription.
Comparison with Similar Compounds
Bendamustine is unique due to its bifunctional nature, combining properties of both alkylating agents and purine analogs . Similar compounds include:
Cyclophosphamide: Another alkylating agent used in chemotherapy.
Melphalan: An alkylating agent used for multiple myeloma.
Chlorambucil: Used for chronic lymphocytic leukemia.
Compared to these compounds, this compound has shown increased stability and a broader range of activity against both quiescent and dividing cells .
Properties
IUPAC Name |
4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C16H21Cl2N3O2/c1-20-14-6-5-12(21(9-7-17)10-8-18)11-13(14)19-15(20)3-2-4-16(22)23/h5-6,11H,2-4,7-10H2,1H3,(H,22,23) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
YTKUWDBFDASYHO-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CN1C2=C(C=C(C=C2)N(CCCl)CCCl)N=C1CCCC(=O)O |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C16H21Cl2N3O2 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
3543-75-7 (hydrochloride) |
Source
|
| Record name | Bendamustine [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0016506277 | |
| 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. | |
DSSTOX Substance ID |
DTXSID2046888 |
Source
|
| Record name | Bendamustine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID2046888 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
358.3 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Mechanism of Action |
Bendamustine is a bifunctional mechlorethamine derivative capable of forming electrophilic alkyl groups that covalently bond to other molecules. Through this function as an alkylating agent, bendamustine causes intra- and inter-strand crosslinks between DNA bases resulting in cell death. It is active against both active and quiescent cells, although the exact mechanism of action is unknown., Multiple myeloma is a fatal hematological disease caused by malignant transformation of plasma cells. Bendamustine has been proven to be a potent alternative to melphalan in phase 3 studies, yet its molecular mode of action is still poorly understood. The four-myeloma cell lines NCI-H929, OPM-2, RPMI-8226, and U266 were cultured in vitro. Apoptosis was measured by flow cytometry after annexin V FITC and propidium iodide staining. Cell cycle distribution of cells was determined by DNA staining with propidium iodide. Intracellular levels of (phosphorylated) proteins were determined by western blot. /It was shown/ that bendamustine induces apoptosis with an IC50 of 35-65 mug/ml and with cleavage of caspase 3. Incubation with 10-30 mug/ml results in G2 cell cycle arrest in all four-cell lines. The primary DNA-damage signaling kinases ATM and Chk2, but not ATR and Chk1, are activated. The Chk2 substrate Cdc25A phosphatase is degraded and Cdc2 is inhibited by inhibitory phosphorylation of Tyr15 accompanied by increased cyclin B levels. Additionally, p53 activation occurs as phosphorylation of Ser15, the phosphorylation site for ATM. p53 promotes Cdc2 inhibition by upregulation of p21. Targeting of p38 MAPK by the selective inhibitor SB202190 significantly increases bendamustine induced apoptosis. Additionally, SB202190 completely abrogates G2 cell cycle arrest. Bendamustine induces ATM-Chk2-Cdc2-mediated G2 arrest and p53 mediated apoptosis. Inhibition of p38 MAPK augments apoptosis and abrogates G2 arrest and can be considered as a new therapeutic strategy in combination with bendamustine., Microarray-based gene expression profiling, real-time PCR, immunoblot, cell cycle, and functional DNA damage repair analyses were used to characterize response to bendamustine and compare it with chlorambucil and phosphoramide mustard. Bendamustine displays a distinct pattern of activity unrelated to other DNA-alkylating agents. Its mechanisms of action include activation of DNA-damage stress response and apoptosis, inhibition of mitotic checkpoints, and induction of mitotic catastrophe. In addition, unlike other alkylators, bendamustine activates a base excision DNA repair pathway rather than an alkyltransferase DNA repair mechanism. These results suggest that bendamustine possesses mechanistic features that differentiate it from other alkylating agents and may contribute to its distinct clinical efficacy profile., Bendamustine is a bifunctional mechlorethamine derivative containing a purine-like benzimidazole ring. Mechlorethamine and its derivatives form electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties, resulting in interstrand DNA crosslinks. The bifunctional covalent linkage can lead to cell death via several pathways. Bendamustine is active against both quiescent and dividing cells. The exact mechanism of action of bendamustine remains unknown. |
Source
|
| Record name | Bendamustine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB06769 | |
| 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 | Bendamustine | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7763 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
CAS No. |
16506-27-7 |
Source
|
| Record name | Bendamustine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=16506-27-7 | |
| 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 | Bendamustine [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0016506277 | |
| 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 | Bendamustine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB06769 | |
| 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 | Bendamustine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID2046888 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | 16506-27-7 | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/information-on-chemicals | |
| 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 | BENDAMUSTINE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/9266D9P3PQ | |
| 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 | Bendamustine | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7763 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Retrosynthesis Analysis
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Strategy Settings
| Precursor scoring | Relevance Heuristic |
|---|---|
| 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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