Identification
- Generic Name
- Methoxyamine
- DrugBank Accession Number
- DB06328
- Background
Not Available
- Type
- Small Molecule
- Groups
- Investigational
- Structure
Structure for Methoxyamine (DB06328)
- Weight
- Average: 47.057
Monoisotopic: 47.037113785 - Chemical Formula
- CH5NO
- Synonyms
- Not Available
- External IDs
- TRC102
Pharmacology
- Indication
Investigated for use/treatment in cancer/tumors (unspecified).
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Not Available
- Mechanism of action
Methoyxamine is investigated for use as an adjunct to alkylating agents, reverse resistance to chemotherapy, and enhancing radiation therapy.
Methoxyamine’s proposed mechanism of action is through blocking of the abasic sites (apurinic/apyrimidinic - AP sites) created by the cleavage of base excision repair (BER) glycoslyates. DNA alkylating agents cause cell death through excessive DNA damage by adduct formation. The human mechanism for DNA repair is very efficient and cancer therapeutics which use this mechanism are often ineffective due to resistance by efficient repair mechanisms such as base excision repair (BER). Alkylating agents such as tezmozolomide form methylated DNA adducts such as O6-methylguanine (O6mG), 7-methylguanine (N7mG) and 3-methyladenine (N3mA). O6mG is a cytotoxic and genotoxic adduct which is repaired by O6-methylguanine DNA-methyltransferase (MGMT). O6mG’s cytotoxicity is due to the mismatch repair mechanism (MMR), but cell induced defects in this repair pathway can lead to drug resistance. The N7mG (dominant lesions caused by methylating agents) and N3mA adducts are both repaired by the BER mechanism. Methoxyamine disrupts the BER pathway, increasing the amount of cytotoxic adducts, which results in cell death. Methoxyamine inhibits BER by stabilizing the AP sites created by cleavage of BER glysosylates, forming MX-AP lesions.Methoxyamine may be an effective adjunct to iododeoxyuridine(IUdR) induced radiosensitization and radiation treatment. IUdR is a halogenated pyrimidine which is incorporated into cellular DNA instead of thymidine, which enhances radiotumor sensitivity. Methoxyamine is proposed to have a dual action in this treatment as it alters cell cycle kinetics as well as prevents repair of DNA by BER, allowing increased sensitivity of tumor cells to DNA damage by radiation therapy. The efficiency of cell cycle repair has been shown to be cell cycle dependent, with the G1 phase being second most sensitive to ionizing radiation (the mitotic, M, phase is the most sensitive). Methoxyamine increases the amount of protein 53 (P53) and protein Rb (pRB), senescence factors which cause the cell to remain in the G1 phase. Methoxyamine also creates a stringent checkpoint at the G1/S boundary as well as an insufficient checkpoint at the G2 stage, preventing cells from going into the S phase. The increased number of G1 cells makes methoxyamine treated tumors more susceptible to ionizing radiation.
The temozolomide and methoxyamine created lesion MX-AP not only disrupts the BER pathway but inhibits topoisomerase II alpha (topo II), an enzyme necessary for DNA replication, recombination and chromosome segregation. MX-AP sites block DNA replication and interfere with choromosome splitting. It is currently uncertain how what the interaction between topoisomerase II and methoxyamine causes cytotoxicity, but several mechanisms have been proposed, such as MX-AP sites binding to topo II, thus reducing their functionality by forming a toxic complex.
Target Actions Organism UDNA Not Available Humans - Absorption
Not Available
- Volume of distribution
Not Available
- Protein binding
Not Available
- Metabolism
- Not Available
- Route of elimination
Not Available
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
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Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Products
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Ingredient UNII CAS InChI Key Methoxyamine hydrochloride 203546OLMF 593-56-6 XNXVOSBNFZWHBV-UHFFFAOYSA-N
Categories
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as organooxygen compounds. These are organic compounds containing a bond between a carbon atom and an oxygen atom.
- Kingdom
- Organic compounds
- Super Class
- Organic oxygen compounds
- Class
- Organooxygen compounds
- Sub Class
- Not Available
- Direct Parent
- Organooxygen compounds
- Alternative Parents
- Organic nitrogen compounds / Hydrocarbon derivatives
- Substituents
- Aliphatic acyclic compound / Hydrocarbon derivative / Organic nitrogen compound / Organooxygen compound
- Molecular Framework
- Aliphatic acyclic compounds
- External Descriptors
- a small molecule (CPD-7648)
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 9TZH4WY30J
- CAS number
- 67-62-9
- InChI Key
- GMPKIPWJBDOURN-UHFFFAOYSA-N
- InChI
- InChI=1S/CH5NO/c1-3-2/h2H2,1H3
- IUPAC Name
- O-methylhydroxylamine
- SMILES
- CON
References
- General References
- Yan L, Bulgar A, Miao Y, Mahajan V, Donze JR, Gerson SL, Liu L: Combined treatment with temozolomide and methoxyamine: blocking apurininc/pyrimidinic site repair coupled with targeting topoisomerase IIalpha. Clin Cancer Res. 2007 Mar 1;13(5):1532-9. [Article]
- Yan T, Seo Y, Schupp JE, Zeng X, Desai AB, Kinsella TJ: Methoxyamine potentiates iododeoxyuridine-induced radiosensitization by altering cell cycle kinetics and enhancing senescence. Mol Cancer Ther. 2006 Apr;5(4):893-902. [Article]
- Liu L, Gerson SL: Therapeutic impact of methoxyamine: blocking repair of abasic sites in the base excision repair pathway. Curr Opin Investig Drugs. 2004 Jun;5(6):623-7. [Article]
- External Links
- ChemSpider
- 3970
- ChEMBL
- CHEMBL1213633
- Wikipedia
- Methoxyamine
Clinical Trials
- Clinical Trials
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
- Not Available
- Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 600.0 mg/mL ALOGPS logP -0.76 ALOGPS logP -0.36 Chemaxon logS 1.11 ALOGPS pKa (Strongest Basic) 4.32 Chemaxon Physiological Charge 0 Chemaxon Hydrogen Acceptor Count 2 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 35.25 Å2 Chemaxon Rotatable Bond Count 0 Chemaxon Refractivity 12.33 m3·mol-1 Chemaxon Polarizability 4.7 Å3 Chemaxon Number of Rings 0 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule Yes Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-0002-9000000000-9145bf1ed99362d118cc Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-0002-9000000000-a073cad6e8629f599f73 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-0002-9000000000-a96f2b5b258fa6941fff Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-0002-9000000000-73b71642646b44867317 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-0002-9000000000-9cf2215e8f4daee08f0c Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-001j-9000000000-72377960e33d464ffb98 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-0002-9000000000-c8cf8ad87feb5ad856eb Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 113.30086 predictedDeepCCS 1.0 (2019) [M+H]+ 115.16089 predictedDeepCCS 1.0 (2019) [M+Na]+ 122.45699 predictedDeepCCS 1.0 (2019)
Targets
Drug created at March 19, 2008 16:24 / Updated at June 12, 2020 16:52