Methoxyamine

This drug entry is a stub and has not been fully annotated. It is scheduled to be annotated soon.

Identification

Name
Methoxyamine
Accession Number
DB06328
Type
Small Molecule
Groups
Investigational
Description
Not Available
Structure
Thumb
Synonyms
  • TRC102
Product Ingredients
IngredientUNIICASInChI Key
Methoxyamine Hydrochloride203546OLMF593-56-6XNXVOSBNFZWHBV-UHFFFAOYSA-N
Categories
UNII
9TZH4WY30J
CAS number
67-62-9
Weight
Average: 47.057
Monoisotopic: 47.037113785
Chemical Formula
CH5NO
InChI Key
GMPKIPWJBDOURN-UHFFFAOYSA-N
InChI
InChI=1S/CH5NO/c1-3-2/h2H2,1H3
IUPAC Name
O-methylhydroxylamine
SMILES
CON

Pharmacology

Indication

Investigated for use/treatment in cancer/tumors (unspecified).

Structured Indications
Not Available
Pharmacodynamics
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.

TargetActionsOrganism
UDNANot AvailableHuman
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
Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:17332299]
  2. 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. [PubMed:16648559]
  3. 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. [PubMed:15242251]
External Links
ChemSpider
3970
ChEMBL
CHEMBL1213633

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedTreatmentAdult Nasal Type Extranodal NK/T-Cell Lymphoma / Anaplastic Large Cell Lymphoma / Angioimmunoblastic T-Cell Lymphoma / Cutaneous B-Cell Non-Hodgkin Lymphoma / Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue / Hepatosplenic T-Cell Lymphoma / Intraocular Lymphoma / Nodal marginal zone B-cell lymphomas / Peripheral T-Cell Lymphoma (PTCL) / Recurrent Adult Burkitt Lymphoma / Recurrent Adult Diffuse Large Cell Lymphoma / Recurrent Adult Diffuse Mixed Cell Lymphoma / Recurrent Adult Diffuse Small Cleaved Cell Lymphoma / Recurrent Adult Grade III Lymphomatoid Granulomatosis / Recurrent Adult Hodgkin's Lymphoma / Recurrent Adult Immunoblastic Large Cell Lymphoma / Recurrent Adult Lymphoblastic Lymphoma / Recurrent Adult T-Cell Leukemia/Lymphoma / Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma / Recurrent Grade 1 Follicular Lymphoma / Recurrent Grade 2 Follicular Lymphoma / Recurrent Grade 3 Follicular Lymphoma / Recurrent Mantle Cell Lymphoma / Recurrent Marginal Zone Lymphoma / Recurrent Mycosis Fungoides/Sezary Syndrome / Recurrent Small Lymphocytic Lymphoma / Refractory Chronic Lymphocytic Leukemia / Refractory Multiple Myeloma / Relapsing Chronic Myelogenous Leukemia / Small Intestine Lymphoma / Splenic Marginal Zone Lymphoma / Stage III Chronic Lymphocytic Leukemia / Testicular Lymphoma / Waldenstrom's Macroglobulinemia (WM)1
1CompletedTreatmentNeoplasms1
1CompletedTreatmentUnspecified Adult Solid Tumor, Protocol Specific1
1RecruitingTreatmentMetastatic Malignant Neoplasm in the Brain / Stage IIIA Large Cell Lung Carcinoma / Stage IIIA Large Cell Lung Carcinoma AJCC v7 / Stage IIIA Lung Adenocarcinoma / Stage IIIA Lung Adenocarcinoma AJCC v7 / Stage IIIA Non-Small Cell Lung Cancer / Stage IIIA Non-Small Cell Lung Cancer AJCC v7 / Stage IIIB Large Cell Lung Carcinoma / Stage IIIB Large Cell Lung Carcinoma AJCC v7 / Stage IIIB Lung Adenocarcinoma / Stage IIIB Lung Adenocarcinoma AJCC v7 / Stage IIIb Non-small Cell Lung Cancer / Stage IIIB Non-Small Cell Lung Cancer AJCC v7 / Stage IV Large Cell Lung Carcinoma / Stage IV Large Cell Lung Carcinoma AJCC v7 / Stage IV Lung Adenocarcinoma / Stage IV Lung Adenocarcinoma AJCC v7 / Stage IV Non-Small Cell Lung Cancer / Stage IV Non-Small Cell Lung Cancer AJCC v71
1, 2RecruitingTreatmentAdvanced Malignant Solid Neoplasm / Advanced Peritoneal Malignant Mesothelioma / Advanced Pleural Malignant Mesothelioma / Advanced thymic carcinoma / Neoplasms, Advanced Solid / Recurrent Malignant Solid Neoplasm / Recurrent Peritoneal Malignant Mesothelioma / Recurrent Pleural Malignant Mesothelioma / Recurrent Solid Neoplasm / Solid Neoplasms / Stage III Non-Small Cell Lung Cancer / Stage III Non-Small Cell Lung Cancer AJCC v7 / Stage III Ovarian Cancer / Stage III Ovarian Cancer AJCC v6 and v7 / Stage III Pleural Malignant Mesothelioma AJCC v7 / Stage III Pleural Mesothelioma / Stage IIIA Non-Small Cell Lung Cancer / Stage IIIA Non-Small Cell Lung Cancer AJCC v7 / Stage IIIA Ovarian Cancer / Stage IIIA Ovarian Cancer AJCC v6 and v7 / Stage IIIb Non-small Cell Lung Cancer / Stage IIIB Non-Small Cell Lung Cancer AJCC v7 / Stage IIIB Ovarian Cancer / Stage IIIB Ovarian Cancer AJCC v6 and v7 / Stage IIIC Ovarian Cancer / Stage IIIC Ovarian Cancer AJCC v6 and v7 / Stage IV Non-Small Cell Lung Cancer / Stage IV Non-Small Cell Lung Cancer AJCC v7 / Stage IV Ovarian Cancer / Stage IV Ovarian Cancer AJCC v6 and v7 / Stage IV Pleural Malignant Mesothelioma AJCC v7 / Stage IV Pleural Mesothelioma / Unresectable Solid Neoplasm1
2Active Not RecruitingTreatmentAdult Brain Glioblastoma1

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
PropertyValueSource
Water Solubility600.0 mg/mLALOGPS
logP-0.76ALOGPS
logP-0.36ChemAxon
logS1.11ALOGPS
pKa (Strongest Basic)4.32ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area35.25 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity12.33 m3·mol-1ChemAxon
Polarizability4.7 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

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
Organic nitrogen compound / Hydrocarbon derivative / Organooxygen compound / Aliphatic acyclic compound
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
a small molecule (CPD-7648)

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Unknown
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da

Drug created on March 19, 2008 10:24 / Updated on January 05, 2018 16:03