, Volume 69, Issue 6, pp 1519-1527
Date: 09 Mar 2012

9-Amino acridine pharmacokinetics, brain distribution, and in vitro/in vivo efficacy against malignant glioma

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The delivery of drugs to the brain is a major obstacle in the design and development of useful treatments for malignant glioma. Previous studies by our laboratory have identified a series of 9-amino acridine compounds that block the catalytic cycle of topoisomerase II resulting in apoptosis and cell death in a variety of cancer cell lines.


This study reports the in vitro and in vivo activity of two promising lead compounds, [{9-[2-(1H-Indol-3-yl)-ethylamino]-acridin-4-yl}-(4-methyl-piperazin-1-yl)-methanone (1) and [9-(1-Benzyl-piperidin-4-ylamino)-acridin-3-yl]-(4-methyl-piperazin-1-yl)-methanone] (2), using an orthotopic glioblastoma mouse model. In addition, the absorption, distribution, and metabolism properties are characterized by determining metabolic stability, MDCK accumulation, Pgp efflux transport, plasma protein binding, and brain distribution in mouse pharmacokinetic studies.


The efficacy results indicate low micromolar ED50 values against glioma cells and a significant increase in the survival of glioma-bearing mice dosed with (2) (p < 0.05). Pharmacokinetic data collected at time intervals following a 60 mg/kg oral dose of acridine 1 and 2 showed both compounds penetrate the blood–brain barrier yielding peak concentrations of 0.25 μM and 0.6 μM, respectively. Peak plasma concentrations were determined to be 2.25 μM (1) and 20.38 μM (2). The results were further compared with data collected using a 15 mg/kg intravenous dose of 2 which yielded a peak concentration in the brain of 1.7 μM at 2.0 h relative to a 2.04 μM peak plasma concentration. The bioavailability was calculated to be 83.8%.


Taken overall, the results suggest compounds in this series may offer new strategies for the design of chemotherapeutics for treating brain cancers with high oral bioavailability and improved efficacy.