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Identification
Name Amsacrine
Accession Number DB00276 (APRD00064)
Type small molecule
Groups approved
Description

Aminoacridine derivative that is a potent intercalating antineoplastic agent. It is effective in the treatment of acute leukemias and malignant lymphomas, but has poor activity in the treatment of solid tumors. It is frequently used in combination with other antineoplastic agents in chemotherapy protocols. It produces consistent but acceptable myelosuppression and cardiotoxic effects. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Acridinyl Anisidide
  • M-AMSA
  • MAMSA
Synonyms
Acridinyl Anisidide
M-AMSA
MAMSA
Salts Not Available
Brand names
Name Company
AMSA P-D
Amsidine
Amsidyl
Amsine
Brand mixtures Not Available
Categories
  • Antineoplastic Agents
  • Intercalating Agents
CAS number 51264-14-3
Weight Average: 393.459
Monoisotopic: 393.114712179
Chemical Formula C21H19N3O3S
InChI Key InChIKey=XCPGHVQEEXUHNC-UHFFFAOYSA-N
InChI
InChI=1S/C21H19N3O3S/c1-27-20-13-14(24-28(2,25)26)11-12-19(20)23-21-15-7-3-5-9-17(15)22-18-10-6-4-8-16(18)21/h3-13,24H,1-2H3,(H,22,23)
Plain Text
IUPAC Name
N-{4-[(acridin-9-yl)amino]-3-methoxyphenyl}methanesulfonamide
SMILES
COC1=C(NC2=C3C=CC=CC3=NC3=CC=CC=C23)C=CC(NS(C)(=O)=O)=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Acridines
Substructures
  • Acridines
  • Aliphatic and Aryl Amines
  • Phenols and Derivatives
  • Pyridines and Derivatives
  • Sulfonyls
  • Ethers
  • Benzene and Derivatives
  • Aminoquinolines and Derivatives
  • Aminopyridines and Derivatives
  • Heterocyclic compounds
  • Aromatic compounds
  • Anisoles
  • (Iso)quinolines and Derivatives
  • Sulfonamides
  • Phenyl Esters
  • Anilines
Pharmacology
Indication For treatment of acute myeloid leukaemia.
Pharmacodynamics Amsacrine is an aminoacridine derivative that is a potent intercalating antineoplastic agent. It is effective in the treatment of acute leukemias and malignant lymphomas, but has poor activity in the treatment of solid tumors. It is frequently used in combination with other antineoplastic agents in chemotherapy protocols. It produces consistent but acceptable myelosuppression and cardiotoxic effects.
Mechanism of action Amsacrine binds to DNA through intercalation and external binding. It has a base specificity for A-T pairs. Rapidly dividing cells are two to four times more sensitive to amsacrine than are resting cells. Amsacrine appears to cleave DNA by inducing double stranded breaks. Amsacrine also targets and inhibits topoisomerase II. Cytotoxicity is greatest during the S phase of the cell cycle when topoisomerase levels are at a maximum.
Absorption Poorly absorbed
Volume of distribution Not Available
Protein binding 96-98%
Metabolism Extensive, primarily hepatic, converted to glutathione conjugate.
Route of elimination Not Available
Half life 8-9 hours
Clearance Not Available
Toxicity Symptoms of overdose include nausea and vomiting, diarrhea, some cardiotoxicity (rarely).
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms
Form Route Strength
Liquid Intravenous
Prices Not Available
Patents Not Available
Properties
State solid
Melting point 234-236oC
Experimental Properties
Property Value Source
water solubility <1 mg/mL PhysProp
logP 3.8 PhysProp
Predicted Properties
Property Value Source
water solubility 3.17e-03 g/l ALOGPS
logP 4.66 ALOGPS
logP 3.16 ChemAxon Molconvert
logS -5.1 ALOGPS
pKa 17.48 ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 2 ChemAxon Molconvert
polar surface area 80.32 ChemAxon Molconvert
rotatable bond count 4 ChemAxon Molconvert
refractivity 107.69 ChemAxon Molconvert
polarizability 41.65 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Link
External Links
Resource Link
KEGG Drug D02321 Link_out
KEGG Compound C01553 Link_out
PubChem Compound 2179 Link_out
PubChem Substance 46507539 Link_out
ChemSpider 2094 Link_out
ChEBI 2687 Link_out
ChEMBL 2687 Link_out
Therapeutic Targets Database DAP000046 Link_out
PharmGKB PA10309 Link_out
Drug Product Database 582212 Link_out
Wikipedia http://en.wikipedia.org/wiki/Amsacrine Link_out
ATC Codes
  • L01XX01
AHFS Codes
  • 10:00.00
PDB Entries Not Available
FDA label Not Available
MSDS show (48.7 KB)
Interactions
Drug Interactions
Drug Interaction
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Food Interactions Not Available
Targets

1. DNA

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.

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. Gabelica V, Rosu F, De Pauw E, Antoine R, Tabarin T, Broyer M, Dugourd P: Electron Photodetachment Dissociation of DNA Anions with Covalently or Noncovalently Bound Chromophores. J Am Soc Mass Spectrom. 2007 Aug 22;. Pubmed
  4. Capranico G, Guano F, Moro S, Zagotto G, Sissi C, Gatto B, Zunino F, Menta E, Palumbo M: Mapping drug interactions at the covalent topoisomerase II-DNA complex by bisantrene/amsacrine congeners. J Biol Chem. 1998 May 22;273(21):12732-9. Pubmed

2. DNA topoisomerase 2-alpha

Pharmacological action: yes
Actions: inhibitor

Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks

Organism class: human
UniProt ID: P11388 Link_out
Gene: TOP2A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Finlay GJ, Atwell GJ, Baguley BC: Inhibition of the action of the topoisomerase II poison amsacrine by simple aniline derivatives: evidence for drug-protein interactions. Oncol Res. 1999;11(6):249-54. Pubmed
  2. Ferlin MG, Marzano C, Chiarelotto G, Baccichetti F, Bordin F: Synthesis and antiproliferative activity of some variously substituted acridine and azacridine derivatives. Eur J Med Chem. 2000 Sep;35(9):827-37. Pubmed
  3. Matsumoto Y, Takano H, Kunishio K, Nagao S, Fojo T: Hypophosphorylation of topoisomerase IIalpha in etoposide (VP-16)-resistant human carcinoma cell lines associated with carboxy-terminal truncation. Jpn J Cancer Res. 2001 Jul;92(7):799-805. Pubmed
  4. Lee MS, Wang JC, Beran M: Two independent amsacrine-resistant human myeloid leukemia cell lines share an identical point mutation in the 170 kDa form of human topoisomerase II. J Mol Biol. 1992 Feb 20;223(4):837-43. Pubmed
  5. Nitiss JL, Liu YX, Harbury P, Jannatipour M, Wasserman R, Wang JC: Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II. Cancer Res. 1992 Aug 15;52(16):4467-72. Pubmed
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  7. Arimondo P, Boukarim C, Bailly C, Dauzonne D, Monneret C: Design of two etoposide-amsacrine conjugates: topoisomerase II and tubuline polymerization inhibition and relation to cytotoxicity. Anticancer Drug Des. 2000 Dec;15(6):413-21. Pubmed

3. Potassium voltage-gated channel subfamily H member 2

Pharmacological action: unknown
Actions: inhibitor

Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoform 3 has no channel activity by itself, but modulates channel characteristics when associated with isoform 1

Organism class: human
UniProt ID: Q12809 Link_out
Gene: KCNH2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Thomas D, Hammerling BC, Wu K, Wimmer AB, Ficker EK, Kirsch GE, Kochan MC, Wible BA, Scholz EP, Zitron E, Kathofer S, Kreye VA, Katus HA, Schoels W, Karle CA, Kiehn J: Inhibition of cardiac HERG currents by the DNA topoisomerase II inhibitor amsacrine: mode of action. Br J Pharmacol. 2004 Jun;142(3):485-94. Epub 2004 May 17. Pubmed
Enzymes

1. Cytochrome P450 2D6

Actions: substrate

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Multidrug resistance protein 1

Actions: inhibitor

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Nagy H, Goda K, Fenyvesi F, Bacso Z, Szilasi M, Kappelmayer J, Lustyik G, Cianfriglia M, Szabo G Jr: Distinct groups of multidrug resistance modulating agents are distinguished by competition of P-glycoprotein-specific antibodies. Biochem Biophys Res Commun. 2004 Mar 19;315(4):942-9. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 14, 2012 11:41