イフォスファミド
概要
説明
イフォスファミドは、精巣がん、軟部肉腫、骨肉腫、膀胱がん、小細胞肺がん、子宮頸がん、卵巣がんなど、さまざまな種類のがんの治療に使用される化学療法薬です . イフォスファミドは、アルキル化剤およびナイトロジェンマスタード薬剤のファミリーに属しています . イフォスファミドは、DNAの複製とRNAの生成を阻害することにより、がん細胞の増殖を阻害します .
製造方法
イフォスファミドは、いくつかの経路を通じて合成することができます。 1つの方法は、イフォスファミド中間体を塩素化剤と反応させ、続いて有機塩基の作用下で環化を行うことです . 別の方法は、アジリジンを出発物質として使用し、環化とそれに続く反応を経てイフォスファミドを形成します . 工業生産方法では、これらの合成経路を最適化し、高収率と高純度を確保すると同時に、有毒で爆発性の化学物質の使用を最小限に抑えることがよくあります .
作用機序
科学的研究の応用
Ifosfamide is widely used in scientific research, particularly in the fields of chemistry, biology, medicine, and industry. In medicine, it is used as a chemotherapeutic agent to treat various cancers . In biology, it is used to study the mechanisms of DNA damage and repair, as well as the effects of alkylating agents on cellular processes . In chemistry, it serves as a model compound for studying the reactivity of nitrogen mustards and the development of new anticancer agents . Industrial applications include the development of nanostructured lipid carriers for oral delivery of ifosfamide, which aim to improve its stability and bioavailability .
生化学分析
Biochemical Properties
Ifosfamide is metabolized by the liver CYP450 enzymes to its active metabolites . These metabolites, phosphoramide mustard derivatives and acrolein, bind to the DNA inhibiting DNA synthesis . The metabolism of Ifosfamide in vivo and in rat liver microsomes is mediated by different CYP isoenzymes: 3A (CYP3A) plus CYP2B1/ CYP2C11 and CYP3A, respectively .
Cellular Effects
Ifosfamide and its metabolites can cause toxicity of normal cells due to induction of oxidative stress . This can lead to hematological toxicity and liver injury .
Molecular Mechanism
The molecular mechanism of Ifosfamide involves its metabolites binding to the DNA, which inhibits DNA synthesis . This action is facilitated by the liver CYP450 enzymes .
Temporal Effects in Laboratory Settings
In most clinical pharmacokinetic studies, the phenomenon of autoinduction has been observed, but the mechanism is not completely understood .
Dosage Effects in Animal Models
The effects of Ifosfamide vary with different dosages in animal models . High doses of Ifosfamide can cause hematological toxicity, oxidative stress, inflammation, and hepatotoxicity .
Metabolic Pathways
Ifosfamide is involved in various metabolic pathways, interacting with enzymes such as CYP3A, CYP2B1, and CYP2C11 . The specific isoenzymes responsible for Ifosfamide metabolism may lead to an improved efficacy/toxicity ratio by modulation of the metabolic pathways .
Transport and Distribution
Whether Ifosfamide is specifically transported by erythrocytes and which activated Ifosfamide metabolites play a key role in this transport is currently being debated .
Subcellular Localization
The subcellular localization of Ifosfamide and its metabolites is a complex process that involves various enzymes and transporters .
準備方法
Ifosfamide can be synthesized through several routes. One method involves reacting an ifosfamide intermediate with a chlorinating agent, followed by cyclization under the action of an organic base . Another method uses aziridine as the starting material, which undergoes cyclization and subsequent reactions to form ifosfamide . Industrial production methods often involve optimizing these synthetic routes to ensure high yield and purity while minimizing the use of toxic and explosive chemicals .
化学反応の分析
イフォスファミドは、酸化、還元、置換など、さまざまな化学反応を受けます。 イフォスファミドは、肝臓でシトクロムP450酵素によって代謝され、活性代謝物と不活性代謝物を生成します . これらの反応に使用される一般的な試薬には、混合機能酸化酵素と有機塩基が含まれます . これらの反応から生成される主要な生成物には、クロロアセトアルデヒドや、薬剤の治療効果と毒性効果に寄与する他の代謝物が含まれます .
科学研究への応用
イフォスファミドは、化学、生物学、医学、産業の分野で広く科学研究に使用されています。 医学では、イフォスファミドは、さまざまながんの治療に使用される化学療法薬です . 生物学では、イフォスファミドは、DNA損傷と修復のメカニズム、およびアルキル化剤の細胞プロセスへの影響を研究するために使用されます . 化学では、イフォスファミドは、ナイトロジェンマスタードの反応性と新規抗がん剤の開発を研究するためのモデル化合物として役立ちます . 工業的な用途には、イフォスファミドの経口投与のためのナノ構造化脂質担体の開発があり、これは安定性とバイオアベイラビリティを向上させることを目的としています .
類似化合物との比較
特性
IUPAC Name |
N,3-bis(2-chloroethyl)-2-oxo-1,3,2λ5-oxazaphosphinan-2-amine |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C7H15Cl2N2O2P/c8-2-4-10-14(12)11(6-3-9)5-1-7-13-14/h1-7H2,(H,10,12) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
HOMGKSMUEGBAAB-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
C1CN(P(=O)(OC1)NCCCl)CCCl |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C7H15Cl2N2O2P |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID7020760 |
Source
|
| Record name | Ifosfamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7020760 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
261.08 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 | Ifosfamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015312 | |
| 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 |
Soluble in water, 1.50e+01 g/L |
Source
|
| Record name | Ifosfamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01181 | |
| 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 | IFOSFAMIDE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7023 | |
| 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. | |
| Record name | Ifosfamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015312 | |
| 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 |
The exact mechanism of ifosfamide has not been determined, but appears to be similar to other alkylating agents. Ifosfamide requires biotransformation in the liver by mixed-function oxidases (cytochrome P450 system) before it becomes active. After metabolic activation, active metabolites of ifosfamide alkylate or bind with many intracellular molecular structures, including nucleic acids. The cytotoxic action is primarily through the alkylation of DNA, done by attaching the N-7 position of guanine to its reactive electrophilic groups. The formation of inter and intra strand cross-links in the DNA results in cell death., Mechanism of action: metabolites cause alkylation of DNA. /from table/, Ifosfamide, a structural analog of cyclophosphamide, belongs to the oxazaphosphorine class of antitumor alkylating agents which must be activated by the mixed function oxidase system of the liver. The 4-hydroxy oxazaphosphorines are a reactive species capable of interacting with nucleic acids & cellular materials to cause cell damage & death. The 4-hydroxy metabolite spontaneously liberates acrolein in many sites throughout the body & it is this substance that is responsible for oxazaphosphorine urotoxicity. Both ifosfamide & cyclophosphamide produce cystitis characterized by tissue edema & ulceration followed by sloughing of mucosal epithelial cells, necrosis of smooth muscle fibers & arteries, & culminating in focal hemorrhage. The selective urotoxicity of oxazaphosphorine occurs because the bladder contains a very low concn of thiol cmpds (glutathione, cysteine) which, by virtue of their nucleophilic sulfhydryl groups, are able to react & neutralize many reactive chemicals. Because the metabolic activation of ifosfamide proceeds more slowly than that of cyclophosphamide, doses of ifosfamide are 3-4 times higher than those of cyclophosphamide. This explains the higher incidence of urotoxicity associated with ifosfamide. |
Source
|
| Record name | Ifosfamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01181 | |
| 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 | IFOSFAMIDE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7023 | |
| 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. | |
Color/Form |
Crystals from anhyd ether, White crystalline powder | |
CAS No. |
3778-73-2 |
Source
|
| Record name | Ifosfamide | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=3778-73-2 | |
| 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 | Ifosfamide [USAN:USP:INN:BAN:JAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0003778732 | |
| 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 | Ifosfamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01181 | |
| 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 | ifosfamide | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=759154 | |
| 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 | ifosfamide | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=109724 | |
| 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 | Ifosfamide | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7020760 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Ifosfamide | |
| Source | European Chemicals Agency (ECHA) | |
| URL | https://echa.europa.eu/substance-information/-/substanceinfo/100.021.126 | |
| 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 | IFOSFAMIDE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/UM20QQM95Y | |
| 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 | IFOSFAMIDE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7023 | |
| 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. | |
| Record name | Ifosfamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015312 | |
| 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 |
39-41 °C, 39 - 41 °C |
Source
|
| Record name | Ifosfamide | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB01181 | |
| 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 | IFOSFAMIDE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7023 | |
| 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. | |
| Record name | Ifosfamide | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015312 | |
| 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. | |
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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