Mechlorethamine

Identification

Name
Mechlorethamine
Accession Number
DB00888
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.

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.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 156.054
Monoisotopic: 155.026854771
Chemical Formula
C5H11Cl2N
Synonyms
  • 2,2'-dichloro-N-methyldiethylamine
  • bis(2-chloroethyl)methylamine
  • bis(β-chloroethyl)methylamine
  • Chlormethine
  • Chlormethinum
  • Clormetina
  • Mechlorethamine
  • methylbis(2-chloroethyl)amine
  • methylbis(β-chloroethyl)amine
  • Mustine
  • N-methyl-bis(2-chloroethyl)amine
  • N-methyl-bis(β-chloroethyl)amine
  • Nitrogen mustard
  • β,β'-dichlorodiethyl-N-methylamine
External IDs
  • NSC-128663

Pharmacology

Indication

For 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.

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Mechlorethamine 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. Mechlorethamine is a nitrogen mustard alkylating agent. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death.

Mechanism of action

Alkylating 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.

TargetActionsOrganism
ADNA
intercalation
Humans
Absorption

Partially absorbed following intracavitary administration, most likely due to rapid deactivation by body fluids. When it is topically administered, systemic exposure was undetectable.

Volume of distribution
Not Available
Protein binding
Not 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 elimination
Not Available
Half-life

15 minutes

Clearance
Not Available
Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

Symptoms 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
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.
DrugInteraction
AbataceptThe risk or severity of adverse effects can be increased when Mechlorethamine is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Mechlorethamine.
AcebutololMechlorethamine may increase the bradycardic activities of Acebutolol.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Mechlorethamine.
AcetylcholineThe risk or severity of adverse effects can be increased when Mechlorethamine is combined with Acetylcholine.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Mechlorethamine.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Mechlorethamine.
AclidiniumMechlorethamine may increase the neuromuscular blocking activities of Aclidinium.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Mechlorethamine.
Adenovirus type 7 vaccine liveThe risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Mechlorethamine.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

Product Ingredients
IngredientUNIICASInChI Key
Mechlorethamine hydrochlorideL0MR697HHI55-86-7QZIQJVCYUQZDIR-UHFFFAOYSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
MustargenPowder, for solution10 mgIntravenousLundbeck Pharmaceuticals Llc1951-12-312011-11-11Canada flag
MustargenPowder, for solution10 mg/10mLIntracavitary; IntravenousRECORDATI RARE DISEASES, INC.1949-03-152019-03-31US flag
MustargenPowder, for solution10 mg/10mLIntracavitary; IntravenousLundbeck Inc.1949-03-152013-04-15US flag
ValchlorGel0.012 g/60gTopicalHelsinn Therapeutics (U.S.), Inc.2018-11-08Not applicableUS flag
ValchlorGel0.012 g/60gTopicalCeptaris Therapeutics, Inc.2013-10-212013-10-22US flag
ValchlorGel0.012 g/60gTopicalActelion Pharmaceuticals US, Inc.2013-10-212020-05-31US flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
L01AA05 — Chlormethine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This 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.
Kingdom
Organic compounds
Super Class
Organic nitrogen compounds
Class
Organonitrogen compounds
Sub Class
Nitrogen mustard compounds
Direct Parent
Nitrogen mustard compounds
Alternative Parents
Trialkylamines / Organopnictogen compounds / Organochlorides / Hydrocarbon derivatives / Alkyl chlorides
Substituents
Aliphatic acyclic compound / Alkyl chloride / Alkyl halide / Amine / Hydrocarbon derivative / Nitrogen mustard / Organochloride / Organohalogen compound / Organopnictogen compound / Tertiary aliphatic amine
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
organochlorine compound, nitrogen mustard (CHEBI:28925)

Chemical Identifiers

UNII
50D9XSG0VR
CAS number
51-75-2
InChI Key
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

References

Synthesis Reference

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

US20030162990
General References
Not Available
Human Metabolome Database
HMDB0015025
KEGG Drug
D07671
KEGG Compound
C07115
PubChem Compound
4033
PubChem Substance
46505784
ChemSpider
3893
BindingDB
200297
RxNav
6674
ChEBI
28925
ChEMBL
CHEMBL427
ZINC
ZINC000002539484
Therapeutic Targets Database
DAP000790
PharmGKB
PA450336
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Chlormethine
FDA label
Download (306 KB)
MSDS
Download (37.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Active Not RecruitingTreatmentDS Stage I Plasma Cell Myeloma / DS Stage II Plasma Cell Myeloma / DS Stage III Plasma Cell Myeloma / Refractory Plasma Cell Myeloma / Smoldering Plasma Cell Myeloma1
3Active Not RecruitingTreatmentLocalized Resectable Neuroblastoma / Localized Unresectable Neuroblastoma / Recurrent Neuroblastoma / Regional Neuroblastoma / Stage 4 Neuroblastoma / Stage 4S Neuroblastoma1
3Active Not RecruitingTreatmentPlasma Cell Myeloma1
3CompletedTreatmentMalignant Lymphomas1
3RecruitingTreatmentGanglioneuroblastoma / INRG Stage L2 / INRG Stage M / INRG Stage MS / Neuroblastomas1
3RecruitingTreatmentRecurrent Diffuse Large B-Cell Lymphoma Activated B-Cell Type / Refractory Diffuse Large B-Cell Lymphoma Activated B-Cell Type1
3Unknown StatusTreatmentMalignant Lymphomas3
2Active Not RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Adult B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL11
2Active Not RecruitingTreatmentGanglioneuroblastoma / High Risk Neuroblastoma1
2Active Not RecruitingTreatmentLymphoma, Hodgkins1

Pharmacoeconomics

Manufacturers
  • Lundbeck inc
Packagers
  • Lundbeck Inc.
  • Merck & Co.
Dosage Forms
FormRouteStrength
GelTopical160 MCG/G
Powder, for solutionIntracavitary; Intravenous10 mg/10mL
Powder, for solutionIntravenous10 mg
GelTopical0.012 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)Region
US7872050No2011-01-182029-07-08US flag
US8501819No2013-08-062026-03-07US flag
US8450375No2013-05-282026-03-07US flag
US8501818No2013-08-062026-03-07US flag
US7838564No2010-11-232026-03-07US flag
US9382191No2016-07-052026-03-07US flag
Additional Data Available
  • Filed On
    Filed On

    The date on which a patent was filed with the relevant government.

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Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)108 - 110°CMSDS
boiling point (°C)87°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 FilterNoChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Download (8.14 KB)
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Mass Spectrum (Electron Ionization)MSsplash10-0a4i-7900000000-66a0ef3007bd03bd9367
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

Targets

Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Intercalation
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Identical protein binding
Specific Function
Esterase with broad substrate specificity. Contributes to the inactivation of the neurotransmitter acetylcholine. Can degrade neurotoxic organophosphate esters.
Gene Name
BCHE
Uniprot ID
P06276
Uniprot Name
Cholinesterase
Molecular Weight
68417.575 Da

Drug created on June 13, 2005 07:24 / Updated on August 27, 2020 19:48

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