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Identification
NameChlorambucil
Accession NumberDB00291  (APRD00115)
TypeSmall Molecule
GroupsApproved
DescriptionA nitrogen mustard alkylating agent used as antineoplastic agent for the treatment of various malignant and nonmalignant diseases. Although it is less toxic than most other nitrogen mustards, it has been listed as a known carcinogen in the Fourth Annual Report on Carcinogens (NTP 85-002, 1985). (Merck Index, 11th ed)
Structure
Thumb
Synonyms
4-(P-Bis(beta-chloroethyl)aminophenyl)butyric acid
4-(p-bis(β-chloroethyl)aminophenyl)butyric acid
4-[p-[bis(2-chloroethyl)amino]phenyl]butyric acid
Ambochlorin
CHLORAMBUCIL
Chloraminophen
gamma-[P-Di(2-chloroethyl)aminophenyl]butyric acid
Leukeran
N,N-Di-2-chloroethyl-gamma-P-aminophenylbutyric acid
N,N-di-2-chloroethyl-γ-p-aminophenylbutyric acid
Phenylbutyric Acid Nitrogen Mustard
γ-[p-di(2-chloroethyl)aminophenyl]butyric acid
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
LeukeranTablet, film coated2 mg/1OralAspen Global Inc.1985-02-13Not applicableUs
LeukeranTablet2 mgOralAspen Pharma Trading Limited1957-12-31Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
CelkeranCelon
ChloraminophèneTechni-Pharma
Brand mixturesNot Available
SaltsNot Available
Categories
UNII18D0SL7309
CAS number305-03-3
WeightAverage: 304.212
Monoisotopic: 303.079284271
Chemical FormulaC14H19Cl2NO2
InChI KeyJCKYGMPEJWAADB-UHFFFAOYSA-N
InChI
InChI=1S/C14H19Cl2NO2/c15-8-10-17(11-9-16)13-6-4-12(5-7-13)2-1-3-14(18)19/h4-7H,1-3,8-11H2,(H,18,19)
IUPAC Name
4-{4-[bis(2-chloroethyl)amino]phenyl}butanoic acid
SMILES
OC(=O)CCCC1=CC=C(C=C1)N(CCCl)CCCl
Pharmacology
IndicationFor treatment of chronic lymphatic (lymphocytic) leukemia, childhood minimal-change nephrotic syndrome, and malignant lymphomas including lymphosarcoma, giant follicular lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas, and Waldenström’s Macroglobulinemia.
Structured Indications
PharmacodynamicsChlorambucil is an antineoplastic in the class of alkylating agents that is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. 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.
TargetKindPharmacological actionActionsOrganismUniProt ID
DNANucleotideunknown
cross-linking/alkylation
Humannot applicabledetails
Related Articles
AbsorptionNot Available
Volume of distributionNot Available
Protein binding99%
MetabolismNot Available
Route of eliminationChlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard. The pharmacokinetic data suggests that oral chlorambucil undergoes rapid gastrointestinal absorption and plasma clearance and that it is almost completely metabolized, having extremely low urinary excretion.
Half life1.5 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
Interactions
Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Chlorambucil.Approved
ALT-110The risk or severity of adverse effects can be increased when Chlorambucil is combined with ALT-110.Investigational
AnvirzelAnvirzel may decrease the cardiotoxic activities of Chlorambucil.Investigational
BcgThe therapeutic efficacy of Bcg can be decreased when used in combination with Chlorambucil.Investigational
BevacizumabBevacizumab may increase the cardiotoxic activities of Chlorambucil.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Chlorambucil.Approved
CDX-110The risk or severity of adverse effects can be increased when Chlorambucil is combined with CDX-110.Investigational
ClozapineThe risk or severity of adverse effects can be increased when Chlorambucil is combined with Clozapine.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Chlorambucil.Approved, Investigational
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Chlorambucil.Approved
DeslanosideDeslanoside may decrease the cardiotoxic activities of Chlorambucil.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Chlorambucil.Approved
DigoxinDigoxin may decrease the cardiotoxic activities of Chlorambucil.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Chlorambucil.Approved, Investigational
FingolimodChlorambucil may increase the immunosuppressive activities of Fingolimod.Approved, Investigational
G17DTThe risk or severity of adverse effects can be increased when Chlorambucil is combined with G17DT.Investigational
GI-5005The risk or severity of adverse effects can be increased when Chlorambucil is combined with GI-5005.Investigational
INGN 201The risk or severity of adverse effects can be increased when Chlorambucil is combined with INGN 201.Investigational
INGN 225The risk or severity of adverse effects can be increased when Chlorambucil is combined with INGN 225.Investigational
LeflunomideThe risk or severity of adverse effects can be increased when Chlorambucil is combined with Leflunomide.Approved, Investigational
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Chlorambucil.Withdrawn
NatalizumabThe risk or severity of adverse effects can be increased when Chlorambucil is combined with Natalizumab.Approved, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Chlorambucil.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Chlorambucil.Approved, Vet Approved
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Chlorambucil.Approved, Investigational
Rabies vaccineThe risk or severity of adverse effects can be increased when Chlorambucil is combined with Rabies vaccine.Approved
Rabies vaccineThe therapeutic efficacy of Rabies vaccine can be decreased when used in combination with Chlorambucil.Approved
RoflumilastRoflumilast may increase the immunosuppressive activities of Chlorambucil.Approved
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Chlorambucil.Approved
SRP 299The risk or severity of adverse effects can be increased when Chlorambucil is combined with SRP 299.Investigational
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Chlorambucil.Approved, Investigational
TG4010The risk or severity of adverse effects can be increased when Chlorambucil is combined with TG4010.Investigational
TofacitinibChlorambucil may increase the immunosuppressive activities of Tofacitinib.Approved, Investigational
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Chlorambucil.Approved, Investigational
Food Interactions
  • Drink liberally.
  • Echinacea should be used with caution, if at all, in patients receiving therapeutic immunosuppressants. Monitor for reduced efficacy of the immunosuppressant during concomitant use.
  • Food reduces bioavailability.
  • Take on an empty stomach.
References
Synthesis Reference

Phillips, A. P. and Mentha, J.W.; U.S.Patent 3,046,301; July 24, 1962; assigned to Burroughs
Wellcome & Co. (U.S.A.) Inc.

US2944079
General References
  1. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L, Hines J, Threatte GA, Larson RA, Cheson BD, Schiffer CA: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med. 2000 Dec 14;343(24):1750-7. [PubMed:11114313 ]
  2. Yang K, Tan J, Wu T: Alkylating agents for Waldenstrom's macroglobulinaemia. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD006719. doi: 10.1002/14651858.CD006719.pub3. [PubMed:19160296 ]
  3. Foon KA, Hallek MJ: Changing paradigms in the treatment of chronic lymphocytic leukemia. Leukemia. 2010 Mar;24(3):500-11. doi: 10.1038/leu.2009.266. Epub 2009 Dec 24. [PubMed:20033051 ]
External Links
ATC CodesL01AA02
AHFS Codes
  • 10:00.00
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (74.6 KB)
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9739
Blood Brain Barrier+0.7889
Caco-2 permeable+0.5734
P-glycoprotein substrateNon-substrate0.6721
P-glycoprotein inhibitor INon-inhibitor0.9394
P-glycoprotein inhibitor IINon-inhibitor0.9222
Renal organic cation transporterNon-inhibitor0.6185
CYP450 2C9 substrateNon-substrate0.7651
CYP450 2D6 substrateNon-substrate0.744
CYP450 3A4 substrateNon-substrate0.6044
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9231
CYP450 2C19 inhibitorNon-inhibitor0.909
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9576
Ames testAMES toxic0.9107
CarcinogenicityNon-carcinogens0.7851
BiodegradationNot ready biodegradable0.9378
Rat acute toxicity3.5709 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.6531
hERG inhibition (predictor II)Non-inhibitor0.8609
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
Manufacturers
  • Smithkline beecham corp dba glaxosmithkline
Packagers
Dosage forms
FormRouteStrength
TabletOral2 mg
Tablet, film coatedOral2 mg/1
Prices
Unit descriptionCostUnit
Leukeran 2 mg tablet3.92USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point65 °CPhysProp
water solubility1.24E+004 mg/LNot Available
logP1.70HANSCH,C ET AL. (1995), pH 7.4
pKa5.75HANSCH,C & LEO,AJ (1987)
Predicted Properties
PropertyValueSource
Water Solubility0.0773 mg/mLALOGPS
logP3.81ALOGPS
logP3.94ChemAxon
logS-3.6ALOGPS
pKa (Strongest Acidic)4.46ChemAxon
pKa (Strongest Basic)1.72ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area40.54 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity79.68 m3·mol-1ChemAxon
Polarizability31.98 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Download (8.25 KB)
Spectra
Spectrum TypeDescriptionSplash Key
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, PositiveNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, NegativeNot Available
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, NegativeNot Available
MSMass Spectrum (Electron Ionization)splash10-0udi-2491000000-ddb7d5da8316562dba36View in MoNA
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
  • Substituted aniline
  • Dialkylarylamine
  • Nitrogen mustard
  • Aniline
  • Benzenoid
  • Monocyclic benzene moiety
  • Tertiary amine
  • Monocarboxylic acid or derivatives
  • Carboxylic acid
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organochloride
  • Organohalogen compound
  • Carbonyl group
  • Amine
  • Alkyl halide
  • Alkyl chloride
  • Aromatic homomonocyclic compound
Molecular FrameworkAromatic homomonocyclic compounds
External Descriptors

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
unknown
Actions
cross-linking/alkylation
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. Begleiter A, Mowat M, Israels LG, Johnston JB: Chlorambucil in chronic lymphocytic leukemia: mechanism of action. Leuk Lymphoma. 1996 Oct;23(3-4):187-201. [PubMed:9031099 ]
  4. Kashiwazaki G, Bando T, Shinohara K, Minoshima M, Kumamoto H, Nishijima S, Sugiyama H: Alkylation of a human telomere sequence by heterotrimeric chlorambucil PI polyamide conjugates. Bioorg Med Chem. 2010 Apr 15;18(8):2887-93. doi: 10.1016/j.bmc.2010.03.011. Epub 2010 Mar 10. [PubMed:20350810 ]
  5. Bielawska A, Bielawski K, Muszynska A: Synthesis and biological evaluation of new cyclic amidine analogs of chlorambucil. Farmaco. 2004 Feb;59(2):111-7. [PubMed:14871502 ]
  6. Minoshima M, Bando T, Shinohara K, Sugiyama H: Molecular design of sequence specific DNA alkylating agents. Nucleic Acids Symp Ser (Oxf). 2009;(53):69-70. doi: 10.1093/nass/nrp035. [PubMed:19749264 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
S-nitrosoglutathione binding
Specific Function:
Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles. Regulates negatively CDK5 activity via p25/p35 translocation to prevent neurodegeneration.
Gene Name:
GSTP1
Uniprot ID:
P09211
Molecular Weight:
23355.625 Da
References
  1. Parker LJ, Ciccone S, Italiano LC, Primavera A, Oakley AJ, Morton CJ, Hancock NC, Bello ML, Parker MW: The anti-cancer drug chlorambucil as a substrate for the human polymorphic enzyme glutathione transferase P1-1: kinetic properties and crystallographic characterisation of allelic variants. J Mol Biol. 2008 Jun 27;380(1):131-44. doi: 10.1016/j.jmb.2008.04.066. Epub 2008 May 4. [PubMed:18511072 ]
  2. Zhang J, Lou YJ: Relationship between activation of microsomal glutathione S-transferase and metabolism behavior of chlorambucil. Pharmacol Res. 2003 Dec;48(6):623-30. [PubMed:14527828 ]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
unknown
General Function:
Sodium-independent organic anion transmembrane transporter activity
Specific Function:
Mediates the Na(+)-independent transport of organic anions such as sulfobromophthalein (BSP) and conjugated (taurocholate) and unconjugated (cholate) bile acids (By similarity). Selectively inhibited by the grapefruit juice component naringin.
Gene Name:
SLCO1A2
Uniprot ID:
P46721
Molecular Weight:
74144.105 Da
References
  1. Kullak-Ublick GA, Glasa J, Boker C, Oswald M, Grutzner U, Hagenbuch B, Stieger B, Meier PJ, Beuers U, Kramer W, Wess G, Paumgartner G: Chlorambucil-taurocholate is transported by bile acid carriers expressed in human hepatocellular carcinomas. Gastroenterology. 1997 Oct;113(4):1295-305. [PubMed:9322525 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on August 17, 2016 12:23