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Identification
NameMechlorethamine
Accession NumberDB00888  (APRD00249)
TypeSmall Molecule
GroupsApproved
Description

A vesicant and necrotizing irritant destructive to mucous membranes, mechlorethamine is an alkylating drug. It was formerly used as a war gas. The hydrochloride is used as an antineoplastic in Hodgkin’s disease and lymphomas. It causes severe gastrointestinal and bone marrow damage. [PubChem]

The FDA granted marketing approval for the orphan drug Valchlor (mechlorethamine) gel on August 23, 2013 for the topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma (CTCL) in patients who have received prior skin-directed therapy. Each tube of Valchlor contains 0.016% of mechlorethamine which is equivalent to 0.02% mechlorethamine HCL.

Structure
Thumb
Synonyms
SynonymLanguageCode
2,2'-dichloro-N-methyldiethylamineNot AvailableNot Available
beta,Beta'-dichlorodiethyl-N-methylamineNot AvailableNot Available
Bis(2-chloroethyl)methylamineNot AvailableNot Available
Bis(beta-chloroethyl)methylamineNot AvailableNot Available
ChlormethineNot AvailableINN
MechlorethamineNot AvailableNot Available
Methylbis(2-chloroethyl)amineNot AvailableNot Available
Methylbis(beta-chloroethyl)amineNot AvailableNot Available
MustineNot AvailableNot Available
N-methyl-bis(2-chloroethyl)amineNot AvailableNot Available
N-Methyl-bis(beta-chloroethyl)amineNot AvailableNot Available
Nitrogen mustardNot AvailableNot Available
β,β'-dichlorodiethyl-N-methylamineNot AvailableNot Available
Salts
Name/CAS Structure Properties
Mechlorethamine hydrochloride
Thumb Not applicable DBSALT000904
Brand names
NameCompany
MustargenRecordati Rare Diseases, Inc.
ValchlorACTELION PHARMS LTD
Brand mixturesNot Available
Categories
CAS number51-75-2
WeightAverage: 156.054
Monoisotopic: 155.026854771
Chemical FormulaC5H11Cl2N
InChI KeyHAWPXGHAZFHHAD-UHFFFAOYSA-N
InChI
InChI=1S/C5H11Cl2N/c1-8(4-2-6)5-3-7/h2-5H2,1H3
IUPAC Name
bis(2-chloroethyl)(methyl)amine
SMILES
CN(CCCl)CCCl
Mass Specshow(8.14 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassOrganonitrogen Compounds
ClassAmines
SubclassTertiary Amines
Direct parentNitrogen Mustard Compounds
Alternative parentsPolyamines; Organochlorides; Alkyl Chlorides
Substituentspolyamine; organohalogen; organochloride; alkyl halide; alkyl chloride
Classification descriptionThis compound belongs to the nitrogen mustard compounds. These are compounds having two beta-haloalkyl groups bound to a phosphorus atom.
Pharmacology
IndicationFor the palliative treatment of Hodgkin's disease (Stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides, and bronchogenic carcinoma. Also for the palliative treatment of metastatic carcinoma resulting in effusion.
PharmacodynamicsMechlorethamine also known as mustine, nitrogen mustard, and HN2, is the prototype anticancer chemotherapeutic drug. Successful clinical use of mechlorethamine gave birth to the field of anticancer chemotherapy. The drug is an analogue of mustard gas and was derived from toxic gas warfare research. It belongs to the group of nitrogen mustard alkylating agents. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.
Mechanism of actionAlkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. Mechlorethamine is cell cycle phase-nonspecific.
AbsorptionPartially absorbed following intracavitary administration, most likely due to rapid deactivation by body fluids. When it is topically administered, systemic exposure was undetectable.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Undergoes rapid chemical transformation and combines with water or reactive compounds of cells, so that the drug is no longer present in active form a few minutes after administration.

Route of eliminationNot Available
Half life15 minutes
ClearanceNot Available
ToxicitySymptoms of overexposure include severe leukopenia, anemia, thrombocytopenia, and a hemorrhagic diathesis with subsequent delayed bleeding may develop. Death may follow. The most common adverse reactions (≥5%) of the topical formulation are dermatitis, pruritus, bacterial skin infection, skin ulceration or blistering, and hyperpigmentation. The oral LD50 for a rat is 10 mg/kg.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption + 0.987
Blood Brain Barrier + 0.9735
Caco-2 permeable + 0.754
P-glycoprotein substrate Non-substrate 0.5964
P-glycoprotein inhibitor I Non-inhibitor 0.9388
P-glycoprotein inhibitor II Non-inhibitor 0.8382
Renal organic cation transporter Inhibitor 0.6023
CYP450 2C9 substrate Non-substrate 0.7811
CYP450 2D6 substrate Non-substrate 0.6069
CYP450 3A4 substrate Non-substrate 0.5986
CYP450 1A2 substrate Non-inhibitor 0.6607
CYP450 2C9 substrate Non-inhibitor 0.9504
CYP450 2D6 substrate Non-inhibitor 0.9153
CYP450 2C19 substrate Non-inhibitor 0.8068
CYP450 3A4 substrate Non-inhibitor 0.9804
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9421
Ames test AMES toxic 0.9108
Carcinogenicity Carcinogens 0.6585
Biodegradation Not ready biodegradable 0.9258
Rat acute toxicity 4.1619 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Strong inhibitor 0.5662
hERG inhibition (predictor II) Non-inhibitor 0.792
Pharmacoeconomics
Manufacturers
  • Lundbeck inc
Packagers
Dosage forms
FormRouteStrength
GelTopical0.016%
Injection, powder, for solutionIntravenous10 mg
Prices
Unit descriptionCostUnit
Mustargen 10 mg vial178.71USDvial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States78385642013-08-232026-03-07
United States78720502013-08-232029-07-08
United States84503752013-08-232026-03-07
United States85018182013-08-232026-03-07
United States85018192013-08-232026-03-07
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point108 - 110°CMSDS
boiling point87°C at 1.80E+01 mm HgPhysProp
water solubilityVery solubleFDA label
logP0.91SELASSIE,CD ET AL. (1990)
pKa6.43 (at 25°C)PERRIN,DD (1965)
Predicted Properties
PropertyValueSource
Water Solubility33.4ALOGPS
logP1.31ALOGPS
logP1.52ChemAxon
logS-0.67ALOGPS
pKa (Strongest Basic)6.08ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area3.24 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity38.67 m3·mol-1ChemAxon
Polarizability15.84 Å3ChemAxon
Number of Rings0ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra
References
Synthesis Reference

Paul Siedlecki, “Preparation of nitrogen mustard derivatives.” U.S. Patent US20030162990, issued August 28, 2003.

US20030162990
General Reference
  1. FDA label
External Links
ResourceLink
KEGG DrugD07671
KEGG CompoundC07115
PubChem Compound4033
PubChem Substance46505784
ChemSpider3893
ChEBI28925
ChEMBLCHEMBL427
Therapeutic Targets DatabaseDAP000790
PharmGKBPA450336
Drug Product Database16063
RxListhttp://www.rxlist.com/cgi/generic3/mustargen.htm
Drugs.comhttp://www.drugs.com/cdi/mechlorethamine.html
WikipediaMechlorethamine
ATC CodesL01AA05D08AX04
AHFS Codes
  • 84:92
  • 10:00.00
PDB EntriesNot Available
FDA labelshow(306 KB)
MSDSshow(37.2 KB)
Interactions
Drug Interactions
Drug
BendamustineIncreases toxicity through pharmacodynamic synergism. Additive myelosuppression.
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food InteractionsNot Available

Targets

1. DNA

Kind: nucleotide

Organism: Human

Pharmacological action: yes

Actions: intercalation

Components

Name UniProt ID Details

References:

  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. Pubmed
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. Pubmed
  3. De Alencar TA, Leitao AC, Lage C: Nitrogen mustard- and half-mustard-induced damage in Escherichia coli requires different DNA repair pathways. Mutat Res. 2005 Apr 4;582(1-2):105-15. Pubmed
  4. Loeber RL, Michaelson-Richie ED, Codreanu SG, Liebler DC, Campbell CR, Tretyakova NY: Proteomic analysis of DNA-protein cross-linking by antitumor nitrogen mustards. Chem Res Toxicol. 2009 Jun;22(6):1151-62. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on November 11, 2013 19:10