Identification

Name
Amsacrine
Accession Number
DB00276  (APRD00064)
Type
Small Molecule
Groups
Approved, Investigational
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
Synonyms
  • 4'-(9-Acridinylamino)-3'-methoxymethanesulfonanilide
  • 4'-(9-Acridinylamino)methanesulfon-m-anisidide
  • 4'-(9-Acridinylamino)methanesulfon-meta-anisidide
  • 4'-(9-Acridinylamino)methanesulphon-m-anisidide
  • Acridinyl anisidide
  • Amsacrine
  • m-AMSA
  • mAMSA
External IDs
CL-880 / NSC-156303 / NSC-249992 / SN-11841 / SN-21429
Product Ingredients
IngredientUNIICASInChI Key
Amsacrine gluconateM4P91439UZ80277-07-2XXNAQBNJPZNRSZ-IFWQJVLJSA-N
Amsacrine hydrochlorideU66HX4K4CO54301-15-4WDISRLXRMMTXEV-UHFFFAOYSA-N
Amsacrine mesylate7LWQ0T63UA54301-16-5KIDGPIWSXHBPDH-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Amsa Pd Inj 50mg/mlLiquid50 mgIntravenousErfa Canada 2012 Inc1983-12-31Not applicableCanada
International/Other Brands
Amekrin / AMSA P-D / Amsidine / Amsidyl
Categories
UNII
00DPD30SOY
CAS number
51264-14-3
Weight
Average: 393.459
Monoisotopic: 393.114712179
Chemical Formula
C21H19N3O3S
InChI Key
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)
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

Pharmacology

Indication

For treatment of acute myeloid leukaemia.

Associated Conditions
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.

TargetActionsOrganism
ADNA
intercalation
Human
ADNA topoisomerase 2-alpha
inhibitor
Human
UPotassium voltage-gated channel subfamily H member 2
inhibitor
Human
UAlpha-1-acid glycoprotein 1Not AvailableHuman
USerum albuminNot AvailableHuman
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
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2-MethoxyethanolThe risk or severity of adverse effects can be increased when Amsacrine is combined with 2-Methoxyethanol.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Amsacrine is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Amsacrine.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Amsacrine.
AbetimusThe risk or severity of adverse effects can be increased when Amsacrine is combined with Abetimus.
AcebutololThe serum concentration of Acebutolol can be increased when it is combined with Amsacrine.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Amsacrine.
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Amsacrine.
Acetylsalicylic acidThe serum concentration of Acetylsalicylic acid can be increased when it is combined with Amsacrine.
ActeosideThe risk or severity of adverse effects can be increased when Amsacrine is combined with Acteoside.
Food Interactions
Not Available

References

General References
  1. Link [Link]
External Links
Human Metabolome Database
HMDB0014421
KEGG Drug
D02321
KEGG Compound
C01553
PubChem Compound
2179
PubChem Substance
46507539
ChemSpider
2094
BindingDB
87351
ChEBI
2687
ChEMBL
CHEMBL43
Therapeutic Targets Database
DAP000046
PharmGKB
PA10309
HET
ASW
Wikipedia
Amsacrine
ATC Codes
L01XX01 — Amsacrine
AHFS Codes
  • 10:00.00 — Antineoplastic Agents
PDB Entries
4g0u
MSDS
Download (48.7 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentLeukemias1
2, 3RecruitingTreatmentLeukemias1
3CompletedTreatmentLeukemias1
3CompletedTreatmentLeukemias / Myelodysplastic Syndromes1
3CompletedTreatmentLeukemias / Neutropenias1
3Unknown StatusTreatmentLeukemias / Neutropenias1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
LiquidIntravenous50 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)235 °CPhysProp
water solubility<1 mg/mLNot Available
logP3.8Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00317 mg/mLALOGPS
logP4.66ALOGPS
logP3.16ChemAxon
logS-5.1ALOGPS
pKa (Strongest Acidic)10.82ChemAxon
pKa (Strongest Basic)8.44ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count5ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area80.32 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity107.69 m3·mol-1ChemAxon
Polarizability41.65 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.667
Caco-2 permeable+0.5
P-glycoprotein substrateNon-substrate0.766
P-glycoprotein inhibitor INon-inhibitor0.5625
P-glycoprotein inhibitor IINon-inhibitor0.7178
Renal organic cation transporterNon-inhibitor0.8983
CYP450 2C9 substrateNon-substrate0.7427
CYP450 2D6 substrateNon-substrate0.8266
CYP450 3A4 substrateNon-substrate0.5159
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorNon-inhibitor0.9232
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.9051
Ames testAMES toxic0.9107
CarcinogenicityNon-carcinogens0.8098
BiodegradationNot ready biodegradable1.0
Rat acute toxicity2.2509 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7711
hERG inhibition (predictor II)Inhibitor0.7355
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 acridines. These are organic compounds containing the acridine moiety, a linear tricyclic heterocycle which consists of two benzene rings joined by a pyridine ring.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Quinolines and derivatives
Sub Class
Benzoquinolines
Direct Parent
Acridines
Alternative Parents
4-aminoquinolines / Sulfanilides / Aminophenyl ethers / Methoxyanilines / Phenoxy compounds / Methoxybenzenes / Anisoles / Alkyl aryl ethers / Aminopyridines and derivatives / Organosulfonamides
show 8 more
Substituents
Acridine / 4-aminoquinoline / Aminoquinoline / Sulfanilide / Aminophenyl ether / Methoxyaniline / Phenoxy compound / Anisole / Phenol ether / Methoxybenzene
show 26 more
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
aromatic ether, sulfonamide, acridines (CHEBI:2687)

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. 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 Nov;18(11):1990-2000. Epub 2007 Aug 22. [PubMed:17900923]
  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:9582297]
Details
2. DNA topoisomerase 2-alpha
Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Inhibitor
General Function
Ubiquitin binding
Specific Function
Control of topological states of DNA by transient breakage and subsequent rejoining of DNA strands. Topoisomerase II makes double-strand breaks. Essential during mitosis and meiosis for proper segr...
Gene Name
TOP2A
Uniprot ID
P11388
Uniprot Name
DNA topoisomerase 2-alpha
Molecular Weight
174383.88 Da
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:10691026]
  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:11006484]
  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:11473732]
  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:1311390]
  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:1322791]
  6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  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:11716434]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function
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 ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da
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:15148258]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Finlay GJ, Baguley BC: Effects of protein binding on the in vitro activity of antitumour acridine derivatives and related anticancer drugs. Cancer Chemother Pharmacol. 2000;45(5):417-22. [PubMed:10803926]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Finlay GJ, Baguley BC: Effects of protein binding on the in vitro activity of antitumour acridine derivatives and related anticancer drugs. Cancer Chemother Pharmacol. 2000;45(5):417-22. [PubMed:10803926]

Enzymes

Details
1. Cytochrome P450 2D6
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256]

Transporters

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
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:14985103]

Drug created on June 13, 2005 07:24 / Updated on September 20, 2018 23:59