Banner
targets (1) enzymes (1)
for drugs
Identification
Name Chlorambucil
Accession Number DB00291 (APRD00115)
Type small molecule
Groups approved
Description

A 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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Chlocambucil
  • Chloraminophen
  • Chloraminophene
  • Chlorbutin
  • Chlorbutine
  • Chloroambucil
  • Chlorobutin
  • Chlorobutine
  • Phenylbutyric Acid Nitrogen Mustard
Brand names
  • Ambochlorin
  • Amboclorin
  • Ecloril
  • Elcoril
  • Leukeran
  • Leukeran Tablets
  • Leukersan
  • Leukoran
  • Linfolizin
  • Linfolysin
  • Pepstatin
Brand name mixtures Not Available
Categories
  • Antineoplastic Agents
  • Antineoplastic Agents, Alkylating
CAS number 305-03-3
Weight Average: 304.212
Monoisotopic: 303.079284271
Chemical Formula C14H19Cl2NO2
InChI Key InChIKey=JCKYGMPEJWAADB-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)
Plain Text
IUPAC Name
4-{4-[bis(2-chloroethyl)amino]phenyl}butanoic acid
SMILES
OC(=O)CCCC1=CC=C(C=C1)N(CCCl)CCCl
Plain Text
Mass Spec show (8.2 KB)
Taxonomy
Kingdom Organic
Classes
  • Nitrogen Mustards
  • Anilines
Substructures
  • Hydroxy Compounds
  • Acetates
  • Aliphatic and Aryl Amines
  • Benzene and Derivatives
  • Carboxylic Acids and Derivatives
  • Alkyl Halides
  • Aromatic compounds
  • Nitrogen Mustards
  • Anilines
Pharmacology
Indication For 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.
Pharmacodynamics Chlorambucil 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 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.
Absorption Not Available
Volume of distribution Not Available
Protein binding 99%
Metabolism
Route of elimination Chlorambucil 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 life 1.5 hours
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Smithkline beecham corp dba glaxosmithkline
Packagers
Dosage forms
Form Route Strength
Tablet Oral
Prices
Unit description Cost Unit
Leukeran 2 mg tablet 3.92 USD tablet
Patents Not Available
Properties
State solid
Melting point 65 oC
Experimental Properties
Property Value Source
water solubility 1.24E+004 mg/L PhysProp
logP 3.9 PhysProp
pKa 5.75 Various sources
Predicted Properties
Property Value Source
water solubility 7.73e-02 g/l ALOGPS
logP 3.81 ALOGPS
logP 3.94 ChemAxon Molconvert
logS -3.59 ALOGPS
pKa ChemAxon Molconvert
hydrogen acceptor count 3 ChemAxon Molconvert
hydrogen donor count 1 ChemAxon Molconvert
polar surface area 40.54 ChemAxon Molconvert
rotatable bond count 9 ChemAxon Molconvert
refractivity 79.68 ChemAxon Molconvert
polarizability 32.24 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  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
  2. Yang K, Tan J, Wu T: Alkylating agents for Waldenstrom’s macroglobulinaemia. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD006719. Pubmed# Foon KA, Hallek MJ: Changing paradigms in the treatment of chronic lymphocytic leukemia. Leukemia. 2010 Mar;24(3):500-11. Epub 2009 Dec 24. Pubmed
External Links
Resource Link
KEGG Drug D00266 Link_out
PubChem Compound 2708 Link_out
PubChem Substance 46506842 Link_out
ChemSpider 2607 Link_out
ChEBI 28830 Link_out
ChEMBL 28830 Link_out
Therapeutic Targets Database DNC001110 Link_out
PharmGKB PA448926 Link_out
Drug Product Database 4626 Link_out
RxList http://www.rxlist.com/cgi/generic2/leukeran.htm Link_out
Drugs.com http://www.drugs.com/cdi/chlorambucil.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Chlorambucil Link_out
ATC Codes
  • L01AA02
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label Not Available
MSDS show (74.6 KB)
Interactions
Drug Interactions Not Available
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.
Targets

1. DNA

Pharmacological action: unknown
Actions: cross-linking/alkylation

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.

Gene Sequence: FASTA

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. 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
  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. Epub 2010 Mar 10. Pubmed
  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
  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. Pubmed
Enzymes

1. Glutathione S-transferase P

Actions: substrate

Conjugation of reduced glutathione to a wide number of exogenous and endogenous hydrophobic electrophiles

UniProt ID: P09211 Link_out
Gene: GSTP1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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. Epub 2008 May 4. Pubmed
  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
Comments
Drug created on June 13, 2005 07:24 / Updated on July 31, 2011 23:19

This project is supported by Genome Alberta & Genome Canada, a not-for-profit organization that is leading Canada's national genomics strategy with $600 million in funding from the federal government. This project is also supported in part by GenomeQuest, Inc., an enterprise genomic information company serving the life science community.