Cancer Chemother Pharmacol (2012) 69:1519–1527 DOI 10.1007/s00280-012-1855-5 123 ORIGINAL ARTICLE 9-Amino acridine pharmacokinetics, brain distribution, and in vitro/in vivo eYcacy against malignant glioma Aaron M. Teitelbaum · Jose L. Gallardo · Jessica Bedi · Rajan Giri · Adam R. Benoit · Michael R. Olin · Kate M. Morizio · John R. Ohlfest · Rory P. Remmel · David M. Ferguson Received: 26 August 2011 / Accepted: 15 February 2012 / Published online: 9 March 2012  Springer-Verlag 2012 Abstract Purpose 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 identiWed 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. Methods 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)-meth- anone (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 eZux transport, plasma protein binding, and brain distribution in mouse pharmacokinetic studies. Results The eYcacy results indicate low micromolar ED 50 values against glioma cells and a signiWcant 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 M and 0.6 M, respectively. Peak plasma concentrations were determined to be 2.25 M (1) and 20.38 M (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 M at 2.0 h relative to a 2.04 M peak plasma concentration. The bioavailability was calculated to be 83.8%. Conclusion Taken overall, the results suggest compounds in this series may oVer new strategies for the design of che- motherapeutics for treating brain cancers with high oral bioavailability and improved eYcacy. Keywords Acridine · Glioma · Anticancer agents · Pharmacokinetics · In vivo eYcacy · Topoisomerase Introduction Annually, more than 14,000 people are diagnosed with pri- mary malignant brain cancer in the United States [1]. In addition, less than 5% of patients with glioblastoma, the most devastating and fatal type of brain malignancy, have survived for 5 years following their initial diagnosis [2]. Treatment for glioblastoma with the administration of the DNA alkylating agent temozolomide (Fig. 1), an oral pro- drug of MTIC (3-methyl-(triazen-1-yl)imidazole-4-carbox- amide), in conjunction with radiotherapy has increased median patient survival to 14.6 months compared with patients receiving radiotherapy alone (12.1 months) [3]. Despite the moderate success of temozolomide treatment, undesirable side eVects such as aplastic anemia [4–6], hepatic encephalopathy [7], and most recently urticarial A. M. Teitelbaum · R. Giri · A. R. Benoit · K. M. Morizio · R. P. Remmel (&) · D. M. Ferguson (&) Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA e-mail: remme001@umn.edu D. M. Ferguson e-mail: ferguson@umn.edu J. L. Gallardo · J. Bedi · M. R. Olin · J. R. Ohlfest (&) Department of Pediatrics and Neurosurgery, Brain Barriers Research Center, University of Minnesota, Minneapolis, MN, USA e-mail: ohlfe001@umn.edu D. M. Ferguson Center for Drug Design, University of Minnesota, Minneapolis, MN, USA