Identification

Name
Troxacitabine
Accession Number
DB04961
Type
Small Molecule
Groups
Investigational
Description

Troxacitabine (brand name Troxatyl) is a nucleoside analogue with anticancer activity. Its use is being studied in patients with refractory lymphoproliferative diseases.

Structure
Thumb
Synonyms
  • (-)-ODDC
External IDs
BCH-4556
International/Other Brands
Troxatyl
Categories
UNII
60KQZ0388Y
CAS number
145918-75-8
Weight
Average: 213.1906
Monoisotopic: 213.074955855
Chemical Formula
C8H11N3O4
InChI Key
RXRGZNYSEHTMHC-BQBZGAKWSA-N
InChI
InChI=1S/C8H11N3O4/c9-5-1-2-11(8(13)10-5)6-4-14-7(3-12)15-6/h1-2,6-7,12H,3-4H2,(H2,9,10,13)/t6-,7-/m0/s1
IUPAC Name
1-[(2S,4S)-2-(hydroxymethyl)-1,3-dioxolan-4-yl]-4-imino-1,4-dihydropyrimidin-2-ol
SMILES
[H][[email protected]]1(CO)OC[[email protected]]([H])(O1)N1C=CC(=N)N=C1O

Pharmacology

Indication

Investigated for use/treatment in leukemia (myeloid).

Structured Indications
Not Available
Pharmacodynamics

Troxacitabine is a beta-L-nucleoside analog, which has shown preclinical antitumor activity in human xenograft tumor models and antileukemic response in patients with relapsed myeloid leukemia.

Mechanism of action

Troxacitabine is activated by cellular kinases and incorporated into DNA, inhibiting its replication. In contrast to other cytosine nucleoside analogs, troxacitabine is resistant to inactivation by cytidine deaminase (CD).

TargetActionsOrganism
UDNANot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity
Not Available
Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Troxacitabine.Approved
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Troxacitabine.Experimental
BevacizumabBevacizumab may increase the cardiotoxic activities of Troxacitabine.Approved, Investigational
CabazitaxelThe risk or severity of adverse effects can be increased when Cabazitaxel is combined with Troxacitabine.Approved
CyclophosphamideCyclophosphamide may increase the cardiotoxic activities of Troxacitabine.Approved, Investigational
CymarinCymarin may decrease the cardiotoxic activities of Troxacitabine.Experimental
DeslanosideDeslanoside may decrease the cardiotoxic activities of Troxacitabine.Approved
DigitoxinDigitoxin may decrease the cardiotoxic activities of Troxacitabine.Approved, Investigational
DigoxinDigoxin may decrease the cardiotoxic activities of Troxacitabine.Approved
Digoxin Immune Fab (Ovine)Digoxin Immune Fab (Ovine) may decrease the cardiotoxic activities of Troxacitabine.Approved
DocetaxelThe risk or severity of adverse effects can be increased when Docetaxel is combined with Troxacitabine.Approved, Investigational
GitoformateGitoformate may decrease the cardiotoxic activities of Troxacitabine.Experimental
Lanatoside CLanatoside C may decrease the cardiotoxic activities of Troxacitabine.Experimental
MetildigoxinMetildigoxin may decrease the cardiotoxic activities of Troxacitabine.Experimental
OleandrinOleandrin may decrease the cardiotoxic activities of Troxacitabine.Experimental, Investigational
OuabainOuabain may decrease the cardiotoxic activities of Troxacitabine.Approved
PaclitaxelThe risk or severity of adverse effects can be increased when Paclitaxel is combined with Troxacitabine.Approved, Vet Approved
PeruvosidePeruvoside may decrease the cardiotoxic activities of Troxacitabine.Experimental
ProscillaridinProscillaridin may decrease the cardiotoxic activities of Troxacitabine.Experimental
TrastuzumabTrastuzumab may increase the cardiotoxic activities of Troxacitabine.Approved, Investigational
Food Interactions
Not Available

References

General References
  1. Lee CK, Rowinsky EK, Li J, Giles F, Moore MJ, Hidalgo M, Capparelli E, Jolivet J, Baker SD: Population pharmacokinetics of troxacitabine, a novel dioxolane nucleoside analogue. Clin Cancer Res. 2006 Apr 1;12(7 Pt 1):2158-65. [PubMed:16609029]
  2. Quintas-Cardama A, Cortes J: Evaluation of the L-stereoisomeric nucleoside analog troxacitabine for the treatment of acute myeloid leukemia. Expert Opin Investig Drugs. 2007 Apr;16(4):547-57. [PubMed:17371201]
  3. Swords R, Giles F: Troxacitabine in acute leukemia. Hematology. 2007 Jun;12(3):219-27. [PubMed:17558697]
  4. Orsolic N, Giles FJ, Gourdeau H, Golemovic M, Beran M, Cortes J, Freireich EJ, Kantarjian H, Verstovsek S: Troxacitabine and imatinib mesylate combination therapy of chronic myeloid leukaemia: preclinical evaluation. Br J Haematol. 2004 Mar;124(6):727-38. [PubMed:15009060]
  5. Boivin AJ, Gourdeau H, Momparler RL: Action of troxacitabine on cells transduced with human cytidine deaminase cDNA. Cancer Invest. 2004;22(1):25-9. [PubMed:15069761]
  6. Kim TE, Park SY, Hsu CH, Dutschman GE, Cheng YC: Synergistic antitumor activity of troxacitabine and camptothecin in selected human cancer cell lines. Mol Pharmacol. 2004 Aug;66(2):285-92. [PubMed:15266019]
External Links
PubChem Compound
454194
PubChem Substance
175426921
ChemSpider
399955
ChEBI
134886
ChEMBL
CHEMBL359164
HET
LTT
Wikipedia
Troxacitabine
PDB Entries
2no9

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2TerminatedTreatmentAcute Myelogenous Leukaemia (AML)1
1, 2TerminatedTreatmentNeoplasms1
2CompletedTreatmentLeukemias1
2TerminatedTreatmentLeukemia Acute Myeloid Leukemia (AML)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 Solubility1.83 mg/mLALOGPS
logP-1.4ALOGPS
logP-0.34ChemAxon
logS-2.1ALOGPS
pKa (Strongest Acidic)9.15ChemAxon
pKa (Strongest Basic)2.43ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count7ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area98.37 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity60.14 m3·mol-1ChemAxon
Polarizability19.94 Å3ChemAxon
Number of Rings2ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9521
Blood Brain Barrier+0.9127
Caco-2 permeable-0.8297
P-glycoprotein substrateNon-substrate0.7729
P-glycoprotein inhibitor INon-inhibitor0.9677
P-glycoprotein inhibitor IINon-inhibitor0.9795
Renal organic cation transporterNon-inhibitor0.9024
CYP450 2C9 substrateNon-substrate0.7935
CYP450 2D6 substrateNon-substrate0.8712
CYP450 3A4 substrateNon-substrate0.6202
CYP450 1A2 substrateNon-inhibitor0.9331
CYP450 2C9 inhibitorNon-inhibitor0.9296
CYP450 2D6 inhibitorNon-inhibitor0.9337
CYP450 2C19 inhibitorNon-inhibitor0.9226
CYP450 3A4 inhibitorNon-inhibitor0.9018
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9516
Ames testNon AMES toxic0.5127
CarcinogenicityNon-carcinogens0.8646
BiodegradationNot ready biodegradable0.9301
Rat acute toxicity1.9792 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9671
hERG inhibition (predictor II)Non-inhibitor0.9287
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 nucleoside and nucleotide analogues. These are analogues of nucleosides and nucleotides. These include phosphonated nucleosides, C-glycosylated nucleoside bases, analogues where the sugar unit is a pyranose, and carbocyclic nucleosides, among others.
Kingdom
Organic compounds
Super Class
Nucleosides, nucleotides, and analogues
Class
Nucleoside and nucleotide analogues
Sub Class
Not Available
Direct Parent
Nucleoside and nucleotide analogues
Alternative Parents
Pyrimidones / Aminopyrimidines and derivatives / Imidolactams / Hydropyrimidines / Heteroaromatic compounds / 1,3-dioxolanes / Oxacyclic compounds / Azacyclic compounds / Acetals / Primary amines
show 4 more
Substituents
Aminopyrimidine / Pyrimidone / Hydropyrimidine / Pyrimidine / Imidolactam / Meta-dioxolane / Heteroaromatic compound / Acetal / Oxacycle / Organoheterocyclic compound
show 13 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
Not Available

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
Unknown
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. Boivin AJ, Gourdeau H, Momparler RL: Action of troxacitabine on cells transduced with human cytidine deaminase cDNA. Cancer Invest. 2004;22(1):25-9. [PubMed:15069761]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Activator
General Function
Protein homodimerization activity
Specific Function
Required for the phosphorylation of the deoxyribonucleosides deoxycytidine (dC), deoxyguanosine (dG) and deoxyadenosine (dA). Has broad substrate specificity, and does not display selectivity based...
Gene Name
DCK
Uniprot ID
P27707
Uniprot Name
Deoxycytidine kinase
Molecular Weight
30518.315 Da
References
  1. Adema AD, Zuurbier L, Floor K, Hubeek I, Kaspers GJ, Albertoni F, Peters GJ: Cellular resistance against troxacitabine in human cell lines and pediatric patient acute myeloid leukemia blast cells. Nucleosides Nucleotides Nucleic Acids. 2006;25(9-11):981-6. [PubMed:17065050]
  2. Adema AD, Radi M, Daft J, Narayanasamy J, Hoebe EK, Alexander LE, Chu CK, Peters GJ: Troxacitabine prodrugs for pancreatic cancer. Nucleosides Nucleotides Nucleic Acids. 2007;26(8-9):1073-7. [PubMed:18058539]

Drug created on October 21, 2007 16:23 / Updated on November 09, 2017 03:49