XR-5000

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C18H19N3O
Molecular Weight	293.363
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN(C)CCNC(=O)C1=CC=CC2=CC3=C(C=CC=C3)N=C12

InChI

InChIKey=XBGNERSKEKDZDS-UHFFFAOYSA-N

InChI=1S/C18H19N3O/c1-21(2)11-10-19-18(22)15-8-5-7-14-12-13-6-3-4-9-16(13)20-17(14)15/h3-9,12H,10-11H2,1-2H3,(H,19,22)

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Description
Sources: https://adisinsight.springer.com/drugs/800002717 | https://www.cancer.gov/publications/dictionaries/cancer-drug/def/acridine-carboxamide | https://www.drugbank.ca/drugs/DB11880

Acridine carboxamide (XR5000) is a tricyclic acridine-based (or carboxamide-based) drug with dual topoisomerase inhibitor and potential antineoplastic activities. Acridine carboxamide inhibits both topoisomerases I and II and intercalates into DNA, resulting in DNA damage, the disruption of DNA repair and replication, the inhibition of RNA and protein synthesis, and cell death. Acridine carboxamide has been used in trials studying the treatment of lung cancer and brain and central nervous system tumors. In clinical trials acridine carboxamide did not show efficacy when tested against various types of cancers.

Originator

Approval Year

PubMed

Title	Date	PubMed
Effects of protein binding on the in vitro activity of antitumour acridine derivatives and related anticancer drugs.	2000	10803926
Individual variation in hepatic aldehyde oxidase activity.	2001 Apr	11569919
Comparative biodistribution and metabolism of carbon-11-labeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and DNA-intercalating analogues.	2001 Apr 1	11306471
Effects of anticancer drugs on the metabolism of the anticancer drug 5,6-dimethylxanthenone-4-acetic (DMXAA) by human liver microsomes.	2001 Aug	11488768
Topoisomerase I/II selectivity among derivatives of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA).	2001 Dec	12375884
Extravascular transport of the DNA intercalator and topoisomerase poison N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (DACA): diffusion and metabolism in multicellular layers of tumor cells.	2001 Jun	11356933
Pharmacokinetic evaluation of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in patients by positron emission tomography.	2001 Mar 1	11230487
Kinetic studies of the binding of acridinecarboxamide topoisomerase poisons to DNA: implications for mode of binding of ligands with uncharged chromophores.	2002 Feb 14	11831901
Inter-strain variability in aldehyde oxidase activity in the mouse.	2002 Jul	12161167
Pharmacokinetics of radiolabelled anticancer drugs for positron emission tomography.	2003	12678875
Mechanisms of action of DNA intercalating acridine-based drugs: how important are contributions from electron transfer and oxidative stress?	2003 Dec	14529454
Use of positron emission tomography in pharmacokinetic studies to investigate therapeutic advantage in a phase I study of 120-hour intravenous infusion XR5000.	2003 Jan 15	12525511
Inhibition of human CYP1A2 oxidation of 5,6-dimethyl-xanthenone-4-acetic acid by acridines: a molecular modelling study.	2005 Aug	16120190
Plasma pharmacokinetic evaluation of cytotoxic agents radiolabelled with positron emitting radioisotopes.	2008 Apr	17639391
Early tumor drug pharmacokinetics is influenced by tumor perfusion but not plasma drug exposure.	2008 Dec 15	19088034
The role of topoisomerases and RNA transcription in the action of the antitumour benzonaphthyridine derivative SN 28049.	2008 Oct	18175117
In vitro assessment of novel transcription inhibitors and topoisomerase poisons in rhabdomyosarcoma cell lines.	2009 Nov	19277661
In vitro-in vivo correlation for intrinsic clearance for drugs metabolized by human aldehyde oxidase.	2010 Aug	20444863

Patents

Sample Use Guides

In Vivo Use Guide

Advanced ovarian cancer: Patients received Acridine carboxamide (XR5000) at the dose of 3010 mg/m(2) through a 120-h central venous infusion every 3 weeks.

Route of Administration: Intravenous

In Vitro Use Guide

CCRF-CEM cells were exposed to a range of concentrations of TAS-103 (0.1 to 10 uM) or Acridine carboxamide (0.1 to 100 uM) for 2 hr and then analysed using the TARDIS assay to detect drug-stabilised topo I, topo IIa, and topo IIb cleavable complexes in individual cells. These cells were sensitive to Acridine carboxamide and TAS-103 with IC50 values of 474 and 5 nM, respectively. Acridine carboxamide showed a dose-dependent increase in topo IIa FITC immunofluorescence levels, with 10 and 100 uM Acridine carboxamide giving significantly higher levels of cleavable complexes than the untreated cells. Only the highest concentration of 100 uM Acridine carboxamide showed any effect on topo IIb FITC immunofluorescence. Topo IIa transformants were found to be more sensitive (Acridine carboxamide IC50=50 uM) than topo IIb transformants (Acridine carboxamide IC50 >137 uM).

Name

Type

Language

XR-5000

Common Name

English

4-ACRIDINECARBOXAMIDE, N-(2-(DIMETHYLAMINO)ETHYL)-

Systematic Name

English

NSC 601316 [WHO-DD]

Common Name

English

N-(2-(DIMETHYLAMINO)ETHYL)ACRIDINE-4-CARBOXAMIDE

Systematic Name

English

NSC-601316

Code

English

XR5000

Code

English

DACA

Common Name

English

ACRIDINE CARBOXAMIDE

Systematic Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1968