Identification

Name
Banoxantrone
Accession Number
DB04975
Type
Small Molecule
Groups
Investigational
Description

Banoxantrone is a highly selective bioreductive drug that is activated in, and is preferentially toxic to, hypoxic cells in tumours. It has been shown to work synergistically with fractionated radiation to significantly delay growth of tumours compared to administration of either banoxantrone or radiation alone. Banoxantrone was also efficacious in tumour models when administered in combination with either cisplatin or chemoradiation. (PMID: 10864207)

Structure
Thumb
Synonyms
  • AQ4N
Categories
UNII
W5H7E45YT3
CAS number
136470-65-0
Weight
Average: 444.488
Monoisotopic: 444.200884638
Chemical Formula
C22H28N4O6
InChI Key
YZBAXVICWUUHGG-UHFFFAOYSA-N
InChI
InChI=1S/C22H28N4O6/c1-25(2,31)11-9-23-13-5-6-14(24-10-12-26(3,4)32)18-17(13)21(29)19-15(27)7-8-16(28)20(19)22(18)30/h5-8,23-24,27-28H,9-12H2,1-4H3
IUPAC Name
2-[(4-{[2-(dimethyl-oxo-$l^{5}-azanyl)ethyl]amino}-5,8-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-1-yl)amino]-N,N-dimethylethanamine oxide
SMILES
C[N+](C)([O-])CCNC1=CC=C(NCC[N+](C)(C)[O-])C2=C1C(=O)C1=C(O)C=CC(O)=C1C2=O

Pharmacology

Indication

For the treatment of various forms of cancer.

Pharmacodynamics

AQ4N was rationally designed to have anti-tumor activity following bioreduction by tissue cytochrome P450 to AQ4, an active DNA topoisomerase II inhibitor. Preclinical studies demonstrated AQ4N selectively targets lymphoid tissues and hypoxic tumor tissues.

Mechanism of action

Banoxantrone (formally known as AQ4N) is preferentially and irreversibly converted to AQ4, its cytotoxic form, in hypoxic tumour cells where it remains localised. When the surrounding oxygenated cells are killed by radiotherapy or chemotherapy bringing these AQ4-containing quiescent cells closer to the oxygen source, they become reoxygenated, attempt to resume replication and, in this state, are killed by AQ4 through potent DNA intercalation and topoisomerase II inhibition.

TargetActionsOrganism
UDNA topoisomerase 2-alphaNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

AQ4N is selectively and irreversibly converted to AQ4, its cytotoxic form, in hypoxic tumor cells, which are its targeted site of action.

Route of elimination
Not Available
Half life

0.64 to 0.83 hours

Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe metabolism of (R)-warfarin can be decreased when combined with Banoxantrone.
(S)-WarfarinThe metabolism of (S)-Warfarin can be decreased when combined with Banoxantrone.
3,5-diiodothyropropionic acidThe metabolism of 3,5-diiodothyropropionic acid can be decreased when combined with Banoxantrone.
4-hydroxycoumarinThe metabolism of 4-hydroxycoumarin can be decreased when combined with Banoxantrone.
5-androstenedioneThe metabolism of Banoxantrone can be decreased when combined with 5-androstenedione.
6-Deoxyerythronolide BThe metabolism of Banoxantrone can be decreased when combined with 6-Deoxyerythronolide B.
6-O-benzylguanineThe metabolism of 6-O-benzylguanine can be decreased when combined with Banoxantrone.
AbemaciclibThe metabolism of Abemaciclib can be decreased when combined with Banoxantrone.
AbirateroneThe metabolism of Abiraterone can be decreased when combined with Banoxantrone.
AcalabrutinibThe metabolism of Banoxantrone can be decreased when combined with Acalabrutinib.
Food Interactions
Not Available

References

General References
  1. McKeown SR, Cowen RL, Williams KJ: Bioreductive drugs: from concept to clinic. Clin Oncol (R Coll Radiol). 2007 Aug;19(6):427-42. Epub 2007 May 4. [PubMed:17482438]
  2. McErlane V, Yakkundi A, McCarthy HO, Hughes CM, Patterson LH, Hirst DG, Robson T, McKeown SR: A cytochrome P450 2B6 meditated gene therapy strategy to enhance the effects of radiation or cyclophosphamide when combined with the bioreductive drug AQ4N. J Gene Med. 2005 Jul;7(7):851-9. [PubMed:15712360]
  3. Atkinson SJ, Loadman PM, Sutton C, Patterson LH, Clench MR: Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumours by imaging matrix-assisted laser desorption/ionisation mass spectrometry. Rapid Commun Mass Spectrom. 2007;21(7):1271-6. [PubMed:17340571]
  4. Lalani AS, Alters SE, Wong A, Albertella MR, Cleland JL, Henner WD: Selective tumor targeting by the hypoxia-activated prodrug AQ4N blocks tumor growth and metastasis in preclinical models of pancreatic cancer. Clin Cancer Res. 2007 Apr 1;13(7):2216-25. [PubMed:17404106]
  5. Patterson LH, McKeown SR, Ruparelia K, Double JA, Bibby MC, Cole S, Stratford IJ: Enhancement of chemotherapy and radiotherapy of murine tumours by AQ4N, a bioreductively activated anti-tumour agent. Br J Cancer. 2000 Jun;82(12):1984-90. [PubMed:10864207]
  6. Loadman PM, Swaine DJ, Bibby MC, Welham KJ, Patterson LH: A preclinical pharmacokinetic study of the bioreductive drug AQ4N. Drug Metab Dispos. 2001 Apr;29(4 Pt 1):422-6. [PubMed:11259326]
External Links
PubChem Compound
9955116
PubChem Substance
347827701
ChemSpider
8130726
ChEMBL
CHEMBL117391

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Unknown StatusTreatmentNon-Hodgkin's Lymphoma (NHL) / Solid Malignancies1
1, 2Unknown StatusTreatmentChronic Lymphocytic Leukaemia (CLL) / Leukemia, Small Lymphocytic / Non-Hodgkin's Lymphoma (NHL)1
1, 2Unknown StatusTreatmentGlioblastoma Multiforme (GBM)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0151 mg/mLALOGPS
logP0.26ALOGPS
logP1.65ChemAxon
logS-4.5ALOGPS
pKa (Strongest Acidic)8.45ChemAxon
pKa (Strongest Basic)4.6ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count8ChemAxon
Hydrogen Donor Count4ChemAxon
Polar Surface Area144.78 Å2ChemAxon
Rotatable Bond Count8ChemAxon
Refractivity125.63 m3·mol-1ChemAxon
Polarizability46.66 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as anthraquinones. These are organic compounds containing either anthracene-9,10-quinone, 1,4-anthraquinone, or 1,2-anthraquinone.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Anthracenes
Sub Class
Anthraquinones
Direct Parent
Anthraquinones
Alternative Parents
Aryl ketones / Secondary alkylarylamines / 1-hydroxy-2-unsubstituted benzenoids / Vinylogous amides / Vinylogous acids / Trialkyl amine oxides / Trisubstituted amine oxides and derivatives / Organic zwitterions / Organic salts / Organic oxides
show 1 more
Substituents
9,10-anthraquinone / Anthraquinone / Aryl ketone / 1-hydroxy-2-unsubstituted benzenoid / Phenol / Secondary aliphatic/aromatic amine / Trialkyl amine oxide / Vinylogous amide / Vinylogous acid / Ketone
show 13 more
Molecular Framework
Aromatic homopolycyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
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. Atkinson SJ, Loadman PM, Sutton C, Patterson LH, Clench MR: Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumours by imaging matrix-assisted laser desorption/ionisation mass spectrometry. Rapid Commun Mass Spectrom. 2007;21(7):1271-6. [PubMed:17340571]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d 24-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
References
  1. Yakkundi A, McErlane V, Murray M, McCarthy HO, Ward C, Hughes CM, Patterson LH, Hirst DG, McKeown SR, Robson T: Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N. Cancer Gene Ther. 2006 Jun;13(6):598-605. [PubMed:16410820]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. McCarthy HO, Yakkundi A, McErlane V, Hughes CM, Keilty G, Murray M, Patterson LH, Hirst DG, McKeown SR, Robson T: Bioreductive GDEPT using cytochrome P450 3A4 in combination with AQ4N. Cancer Gene Ther. 2003 Jan;10(1):40-8. [PubMed:12489027]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Yakkundi A, McErlane V, Murray M, McCarthy HO, Ward C, Hughes CM, Patterson LH, Hirst DG, McKeown SR, Robson T: Tumor-selective drug activation: a GDEPT approach utilizing cytochrome P450 1A1 and AQ4N. Cancer Gene Ther. 2006 Jun;13(6):598-605. [PubMed:16410820]
  2. McErlane V, Yakkundi A, McCarthy HO, Hughes CM, Patterson LH, Hirst DG, Robson T, McKeown SR: A cytochrome P450 2B6 meditated gene therapy strategy to enhance the effects of radiation or cyclophosphamide when combined with the bioreductive drug AQ4N. J Gene Med. 2005 Jul;7(7):851-9. [PubMed:15712360]

Drug created on October 21, 2007 16:23 / Updated on November 02, 2018 06:07