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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
2,2'-dichloro-N-methyldiethylamine
beta,Beta'-dichlorodiethyl-N-methylamine
Bis(2-chloroethyl)methylamine
Bis(beta-chloroethyl)methylamine
Chlormethine
Mechlorethamine
Methylbis(2-chloroethyl)amine
Methylbis(beta-chloroethyl)amine
Mustine
N-methyl-bis(2-chloroethyl)amine
N-Methyl-bis(beta-chloroethyl)amine
Nitrogen mustard
β,β'-dichlorodiethyl-N-methylamine
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Mustargenpowder for solution10 mgintravenousLundbeck LLC1951-12-312011-11-11Canada
Mustargenpowder, for solution10 mg/10mLintracavitary; intravenousRECORDATI RARE DISEASES, INC.1949-03-15Not applicableUs
Valchlorgel.012 g/60gtopicalCeptaris Therapeutics, Inc.2013-10-21Not applicableUs
Valchlorgel.012 g/60gtopicalActelion Pharmaceuticals US, Inc.2013-10-21Not applicableUs
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Mechlorethamine hydrochloride
ThumbNot applicableDBSALT000904
Categories
UNII50D9XSG0VR
CAS number51-75-2
WeightAverage: 156.054
Monoisotopic: 155.026854771
Chemical FormulaC5H11Cl2N
InChI KeyInChIKey=HAWPXGHAZFHHAD-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
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as nitrogen mustard compounds. These are compounds having two beta-haloalkyl groups bound to a nitrogen atom.
KingdomOrganic compounds
Super ClassOrganonitrogen compounds
ClassNitrogen mustard compounds
Sub ClassNot Available
Direct ParentNitrogen mustard compounds
Alternative Parents
Substituents
  • Nitrogen mustard
  • Tertiary aliphatic amine
  • Tertiary amine
  • Hydrocarbon derivative
  • Organochloride
  • Organohalogen compound
  • Amine
  • Alkyl halide
  • Alkyl chloride
  • Aliphatic acyclic compound
Molecular FrameworkAliphatic acyclic compounds
External Descriptors
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.
Related Articles
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
PropertyValueProbability
Human Intestinal Absorption+0.987
Blood Brain Barrier+0.9735
Caco-2 permeable+0.754
P-glycoprotein substrateNon-substrate0.5964
P-glycoprotein inhibitor INon-inhibitor0.9388
P-glycoprotein inhibitor IINon-inhibitor0.8382
Renal organic cation transporterInhibitor0.6023
CYP450 2C9 substrateNon-substrate0.7811
CYP450 2D6 substrateNon-substrate0.6069
CYP450 3A4 substrateNon-substrate0.5986
CYP450 1A2 substrateNon-inhibitor0.6607
CYP450 2C9 inhibitorNon-inhibitor0.9504
CYP450 2D6 inhibitorNon-inhibitor0.9153
CYP450 2C19 inhibitorNon-inhibitor0.8068
CYP450 3A4 inhibitorNon-inhibitor0.9804
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9421
Ames testAMES toxic0.9108
CarcinogenicityCarcinogens 0.6585
BiodegradationNot ready biodegradable0.9258
Rat acute toxicity4.1619 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.5662
hERG inhibition (predictor II)Non-inhibitor0.792
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Lundbeck inc
Packagers
Dosage forms
FormRouteStrength
Powder for solutionintravenous10 mg
Powder, for solutionintracavitary; intravenous10 mg/10mL
Geltopical.012 g/60g
Prices
Unit descriptionCostUnit
Mustargen 10 mg vial178.71USD vial
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7838564 No2006-03-072026-03-07Us
US7872050 No2009-07-082029-07-08Us
US8450375 No2006-03-072026-03-07Us
US8501818 No2006-03-072026-03-07Us
US8501819 No2006-03-072026-03-07Us
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 Solubility33.4 mg/mLALOGPS
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 FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (8.14 KB)
Spectra
Spectrum TypeDescriptionSplash Key
MSMass Spectrum (Electron Ionization)splash10-0a4i-7900000000-66a0ef3007bd03bd9367View in MoNA
References
Synthesis Reference

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

US20030162990
General ReferencesNot Available
External Links
ATC CodesL01AA05
AHFS Codes
  • 10:00.00
  • 84:92
PDB EntriesNot Available
FDA labelDownload (306 KB)
MSDSDownload (37.2 KB)
Interactions
Drug Interactions
Drug
ClozapineThe risk or severity of adverse effects can be increased when Mechlorethamine is combined with Clozapine.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Mechlorethamine.
LeflunomideThe risk or severity of adverse effects can be increased when Mechlorethamine is combined with Leflunomide.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Mechlorethamine.
NatalizumabThe risk or severity of adverse effects can be increased when Mechlorethamine is combined with Natalizumab.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Mechlorethamine.
RoflumilastRoflumilast may increase the immunosuppressive activities of Mechlorethamine.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Mechlorethamine.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Mechlorethamine.
TofacitinibMechlorethamine may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Mechlorethamine.
Food InteractionsNot Available

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
intercalation
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
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:17139284 ]
  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:17016423 ]
  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:15781216 ]
  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. doi: 10.1021/tx900078y. [PubMed:19480393 ]
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Drug created on June 13, 2005 07:24 / Updated on July 30, 2016 01:53