Mechlorethamine

Identification

Name
Mechlorethamine
Accession Number
DB00888  (APRD00249)
Type
Small Molecule
Groups
Approved
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 IDs
NSC-128663
Product Ingredients
IngredientUNIICASInChI Key
Mechlorethamine hydrochlorideL0MR697HHI55-86-7QZIQJVCYUQZDIR-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MustargenPowder, for solution10 mgIntravenousLundbeck Inc.1951-12-312011-11-11Canada
MustargenPowder, for solution10 mg/10mLIntracavitary; IntravenousRecordati Rare Diseases Inc1949-03-15Not applicableUs
ValchlorGel.012 g/60gTopicalCeptaris Therapeutics, Inc.2013-10-212017-10-17Us
ValchlorGel.012 g/60gTopicalActelion2013-10-21Not applicableUs
Categories
UNII
50D9XSG0VR
CAS number
51-75-2
Weight
Average: 156.054
Monoisotopic: 155.026854771
Chemical Formula
C5H11Cl2N
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

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.

Structured Indications
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. 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 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
Human
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
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
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Mechlorethamine.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Mechlorethamine.Experimental
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Mechlorethamine.Investigational
BevacizumabBevacizumab may increase the cardiotoxic activities of Mechlorethamine.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Mechlorethamine.Approved
Clostridium tetani toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Clostridium tetani toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Mechlorethamine.Approved
ClozapineThe risk or severity of adverse effects can be increased when Mechlorethamine is combined with Clozapine.Approved
Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated)The therapeutic efficacy of Corynebacterium diphtheriae toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Mechlorethamine.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Mechlorethamine.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Mechlorethamine.Experimental
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Mechlorethamine.Approved
DeslanosideDeslanoside may decrease the cardiotoxic activities of Mechlorethamine.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Mechlorethamine.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Mechlorethamine.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Mechlorethamine.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Mechlorethamine.Approved, Investigational
FingolimodMechlorethamine may increase the immunosuppressive activities of Fingolimod.Approved, Investigational
G17DTThe therapeutic efficacy of G17DT can be decreased when used in combination with Mechlorethamine.Investigational
GI-5005The therapeutic efficacy of GI-5005 can be decreased when used in combination with Mechlorethamine.Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Mechlorethamine.Experimental
Hepatitis A VaccineThe therapeutic efficacy of Hepatitis A Vaccine can be decreased when used in combination with Mechlorethamine.Approved
Hepatitis B Vaccine (Recombinant)The therapeutic efficacy of Hepatitis B Vaccine (Recombinant) can be decreased when used in combination with Mechlorethamine.Approved, Withdrawn
INGN 201The therapeutic efficacy of INGN 201 can be decreased when used in combination with Mechlorethamine.Investigational
INGN 225The therapeutic efficacy of INGN 225 can be decreased when used in combination with Mechlorethamine.Investigational
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Mechlorethamine.Experimental
LeflunomideThe risk or severity of adverse effects can be increased when Mechlorethamine is combined with Leflunomide.Approved, Investigational
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Mechlorethamine.Investigational, Withdrawn
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Mechlorethamine.Experimental
NatalizumabThe risk or severity of adverse effects can be increased when Mechlorethamine is combined with Natalizumab.Approved, Investigational
OleandrinOleandrin may decrease the cardiotoxic activities of Mechlorethamine.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Mechlorethamine.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Mechlorethamine.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Mechlorethamine.Experimental
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Mechlorethamine.Approved, Investigational
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Mechlorethamine.Experimental
Rabies virus inactivated antigen, AThe risk or severity of adverse effects can be increased when Mechlorethamine is combined with Rabies virus inactivated antigen, A.Approved
Rabies virus inactivated antigen, AThe therapeutic efficacy of Rabies virus inactivated antigen, A can be decreased when used in combination with Mechlorethamine.Approved
RindopepimutThe therapeutic efficacy of Rindopepimut can be decreased when used in combination with Mechlorethamine.Investigational
RoflumilastRoflumilast may increase the immunosuppressive activities of Mechlorethamine.Approved
Rotavirus VaccineThe therapeutic efficacy of Rotavirus Vaccine can be decreased when used in combination with Mechlorethamine.Approved
Rubella virus vaccineThe therapeutic efficacy of Rubella virus vaccine can be decreased when used in combination with Mechlorethamine.Approved
Salmonella typhi ty21a live antigenThe therapeutic efficacy of Salmonella typhi ty21a live antigen can be decreased when used in combination with Mechlorethamine.Approved
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Mechlorethamine.Approved
SRP 299The therapeutic efficacy of SRP 299 can be decreased when used in combination with Mechlorethamine.Investigational
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Mechlorethamine.Approved, Investigational
TecemotideThe therapeutic efficacy of Tecemotide can be decreased when used in combination with Mechlorethamine.Investigational
TG4010The therapeutic efficacy of TG4010 can be decreased when used in combination with Mechlorethamine.Investigational
TofacitinibMechlorethamine may increase the immunosuppressive activities of Tofacitinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Mechlorethamine.Approved, Investigational
Varicella Zoster Vaccine (Live/Attenuated)The therapeutic efficacy of Zoster vaccine can be decreased when used in combination with Mechlorethamine.Approved
Yellow fever vaccineThe therapeutic efficacy of Yellow fever vaccine can be decreased when used in combination with Mechlorethamine.Approved
Food Interactions
Not Available

References

Synthesis Reference

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

US20030162990
General References
Not Available
External Links
Human Metabolome Database
HMDB15025
KEGG Drug
D07671
KEGG Compound
C07115
PubChem Compound
4033
PubChem Substance
46505784
ChemSpider
3893
BindingDB
200297
ChEBI
28925
ChEMBL
CHEMBL427
Therapeutic Targets Database
DAP000790
PharmGKB
PA450336
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Mechlorethamine
ATC Codes
L01AA05 — Chlormethine
FDA label
Download (306 KB)
MSDS
Download (37.2 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
0RecruitingSupportive CareSkin Irritation1
2Active Not RecruitingTreatmentLymphoma, Hodgkins1
2Active Not RecruitingTreatmentMalignant Lymphomas1
2CompletedTreatmentBrain and Central Nervous System Tumors1
2CompletedTreatmentMalignant Lymphomas1
2CompletedTreatmentMycosis Fungoides (MF)2
2Not Yet RecruitingTreatmentCutaneous T-Cell Lymphoma (CTCL) / Mycosis Fungoides (MF)1
2Not Yet RecruitingTreatmentMycosis Fungoides (MF)1
2Unknown StatusTreatmentMalignant Lymphomas2
3Active Not RecruitingTreatmentMalignant Lymphomas2
3CompletedTreatmentMalignant Lymphomas1
3Unknown StatusTreatmentMalignant Lymphomas1
Not AvailableRecruitingNot AvailableMycosis Fungoides (MF)1

Pharmacoeconomics

Manufacturers
  • Lundbeck inc
Packagers
Dosage forms
FormRouteStrength
Powder, for solutionIntracavitary; Intravenous10 mg/10mL
Powder, for solutionIntravenous10 mg
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)
US7872050No2009-07-082029-07-08Us
US8501819No2006-03-072026-03-07Us
US8450375No2006-03-072026-03-07Us
US8501818No2006-03-072026-03-07Us
US7838564No2006-03-072026-03-07Us
US9382191No2006-03-072026-03-07Us

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

Taxonomy

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
Nitrogen mustard / Tertiary aliphatic amine / Tertiary amine / Organopnictogen compound / Hydrocarbon derivative / Organochloride / Organohalogen compound / Amine / Alkyl halide / Alkyl chloride
Molecular Framework
Aliphatic acyclic compounds
External Descriptors
organochlorine compound, nitrogen mustard (CHEBI:28925)

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]

Drug created on June 13, 2005 07:24 / Updated on December 01, 2017 17:17