Miltefosine
Overview
Description
Miltefosine is a broad-spectrum antimicrobial and antileishmanial agent. Originally developed in the 1980s as an anti-cancer drug, it is now primarily used to treat leishmaniasis, a disease caused by parasites of the Leishmania type. This compound is the first and only oral drug approved for the treatment of visceral, cutaneous, and mucosal forms of leishmaniasis . It is also used off-label to treat infections caused by free-living amoebae .
Scientific Research Applications
Safety and Hazards
Mechanism of Action
Miltefosine is an alkylphosphocholine drug with demonstrated activity against various parasite species and cancer cells . It is the only oral drug approved for the treatment of Leishmaniasis and American Trypanosomiasis (Chagas disease) .
Target of Action
This compound’s primary targets are the Leishmania parasites and neoplastic cells . It has a broad-spectrum anti-parasitic effect, primarily disrupting the intracellular Ca2+ homeostasis of the parasites while sparing the human hosts .
Mode of Action
This compound interacts with its targets primarily through two mechanisms :
- Apoptosis : this compound induces apoptosis-like cell death in its targets .
- Disturbance of lipid-dependent cell signaling pathways : this compound interferes with the functioning of several enzymes involved in phospholipid metabolism .
Biochemical Pathways
This compound affects the unique giant mitochondria and the acidocalcisomes of parasites, both of which are involved in Ca2+ regulation . It inhibits phosphatidylcholine biosynthesis in mammalian cells, primarily via the Kennedy CDP–Choline pathway, by blocking phosphocholine citidyltransferase . In Trypanosoma cruzi, this compound inhibits the Greenberg (transmethylation) pathway by acting on phosphatidylethanolamine N methyl-transferase .
Pharmacokinetics
This compound is characterized by slow absorption and elimination, leading to long initial (approximately 7 days) and terminal (approximately 30 days) half-lives . It is not a substrate of cytochrome P450 metabolic enzymes and only 0.2% of the administered dose is eliminated in the urine at day 23 of a 28-day treatment regimen . The absorption of this compound is concentration-dependent, with passive paracellular diffusion applicable to the concentration below 20.4 μg/mL .
Result of Action
This compound exhibits broad-spectrum anti-parasitic effects primarily by disrupting the intracellular Ca2+ homeostasis of the parasites . It also positively affects the host’s immune system . The drug interferes with biosynthesis of phospholipids and metabolism of alkyl-lipids . It is known to cause cell shrinkage, nuclear DNA condensation, and DNA fragmentation resulting in apoptosis-like cell death in L. donovani .
Action Environment
It is known that the drug’s therapeutic effect extends beyond its impact on the parasite to also positively affect the host’s immune system . These findings suggest a complex interplay between drug susceptibility, neutrophil activation, and Leishmania survival .
Biochemical Analysis
Biochemical Properties
Miltefosine plays a significant role in biochemical reactions. It interacts with various enzymes, proteins, and other biomolecules. The compound is metabolized mainly by phospholipase D, releasing choline, choline-containing metabolites, and hexadecanol . These metabolites are all endogenous and are likely used for the biosynthesis of acetylcholine, cell membranes, and long-chain fatty acids .
Cellular Effects
This compound has profound effects on various types of cells and cellular processes. It influences cell function, including impacts on cell signaling pathways, gene expression, and cellular metabolism . It has been found to affect the unique giant mitochondria and the acidocalcisomes of parasites, both of which are involved in Ca 2+ regulation .
Molecular Mechanism
The molecular mechanism of action of this compound involves its binding interactions with biomolecules, enzyme inhibition or activation, and changes in gene expression . In addition to its inhibitory effects on phosphatidylcholine synthesis and cytochrome c oxidase, this compound has been found to affect the unique giant mitochondria and the acidocalcisomes of parasites .
Dosage Effects in Animal Models
The effects of this compound vary with different dosages in animal models . This includes any threshold effects observed in these studies, as well as any toxic or adverse effects at high doses .
Metabolic Pathways
This compound is involved in several metabolic pathways. It interacts with enzymes or cofactors, and it can also affect metabolic flux or metabolite levels .
Transport and Distribution
This compound is transported and distributed within cells and tissues . This includes any transporters or binding proteins that it interacts with, as well as any effects on its localization or accumulation .
Subcellular Localization
This could include any targeting signals or post-translational modifications that direct it to specific compartments or organelles .
Preparation Methods
Synthetic Routes and Reaction Conditions
Miltefosine can be synthesized through a multi-step process. One common method involves the reaction of cetyl alcohol with triethylamine and trichlorine phosphine oxide in tetrahydrofuran. This is followed by the addition of dimethylethanolamine and triethylamine to obtain cetyl phosphamide .
Industrial Production Methods
The industrial production of this compound typically involves large-scale synthesis using similar chemical reactions as described above. The process is optimized for high yield and purity, ensuring that the final product meets pharmaceutical standards .
Chemical Reactions Analysis
Types of Reactions
Miltefosine undergoes various chemical reactions, including oxidation, reduction, and substitution. These reactions are essential for its metabolism and biological activity .
Common Reagents and Conditions
Common reagents used in the reactions involving this compound include oxidizing agents, reducing agents, and various solvents. The conditions for these reactions are carefully controlled to ensure the desired outcomes .
Major Products Formed
The major products formed from the reactions of this compound depend on the specific reagents and conditions used. For example, oxidation reactions may produce different metabolites that contribute to its therapeutic effects .
Comparison with Similar Compounds
Miltefosine belongs to the class of alkylphosphocholine compounds. Similar compounds include hexadecylphosphocholine and other alkylglycerophosphocholines. These compounds share structural similarities but differ in their alkyl chain length and backbone structure . This compound’s unique combination of properties makes it particularly effective against leishmaniasis and other parasitic infections .
List of Similar Compounds
- Hexadecylphosphocholine
- Alkylglycerophosphocholines
- Ether lipids
This compound stands out due to its oral bioavailability and broad-spectrum activity, making it a valuable tool in the fight against parasitic diseases .
Properties
IUPAC Name |
hexadecyl 2-(trimethylazaniumyl)ethyl phosphate |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C21H46NO4P/c1-5-6-7-8-9-10-11-12-13-14-15-16-17-18-20-25-27(23,24)26-21-19-22(2,3)4/h5-21H2,1-4H3 |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
PQLXHQMOHUQAKB-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CCCCCCCCCCCCCCCCOP(=O)([O-])OCC[N+](C)(C)C |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C21H46NO4P |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
DSSTOX Substance ID |
DTXSID7045942 |
Source
|
| Record name | Miltefosine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7045942 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
407.6 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Mechanism of Action |
Miltefosine has demonstrated activity against Leishmania parasites and neoplastic cells primarily due to its effects on apoptosis and disturbance of lipid-dependent cell signalling pathways. Several potential antileishmanial mechanisms of action have been proposed, however no mechanism has been identified definitely. Within the mitochondria, miltefosine inhibits cytochrome-c oxidase leading to mitochondrial dysfunction and apoptosis-like cell death. Antineoplastic mechanisms of action are related to antileishmanial targets and include inhibition of phosphatidylcholine biosynthesis and inhibition of Akt (also known as protein kinase B), which is a crucial protein within the PI3K/Akt/mTOR intracellular signalling pathway involved in regulating the cell cycle. Animal studies also suggest it may be effective against Trypanosome cruzi (the organism responsible for Chagas' disease), metronidazole-resistant strains of Trichonomas vaginalis, and it may have broad-spectrum anti-fungal activity. |
Source
|
| Record name | Miltefosine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09031 | |
| 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. |
58066-85-6 |
Source
|
| Record name | Miltefosine | |
| Source | CAS Common Chemistry | |
| URL | https://commonchemistry.cas.org/detail?cas_rn=58066-85-6 | |
| 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 | Miltefosine [INN:BAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0058066856 | |
| 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 | Miltefosine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB09031 | |
| 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 | Miltefosine | |
| Source | DTP/NCI | |
| URL | https://dtp.cancer.gov/dtpstandard/servlet/dwindex?searchtype=NSC&outputformat=html&searchlist=758968 | |
| 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 | Miltefosine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID7045942 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
| Record name | Miltefosine | |
| 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 | MILTEFOSINE | |
| Source | FDA Global Substance Registration System (GSRS) | |
| URL | https://gsrs.ncats.nih.gov/ginas/app/beta/substances/53EY29W7EC | |
| 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. | |
Retrosynthesis Analysis
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Strategy Settings
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|---|---|
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| Model | Template_relevance |
| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
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