Send Orders for Reprints to reprints@benthamscience.ae Letters in Organic Chemistry, 2015, 12, 319-323 319 Synthesis and Cytotoxicity of 4-(2-Adamantyl)phenylalkylamines Ioannis Papanastasiou a,* , Stefanos Riganas a , George B. Foscolos a , Andrew Tsotinis a , Samar A. Akhtar b , Mohsin A. Khan b , Khondaker M. Rahman b,* and David E. Thurston b a School of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 84 Athens, Greece; b Institute of Pharmaceutical Science, King’s College London, Britannia House, 7 Trinity Street, London SE1 1DB, UK Received October 01, 2014: Revised January 19, 2015: Accepted February 03, 2015 Abstract: The design and synthesis of 4-(2-adamantyl)phenylalkylamines 1-4 are described and their antiproliferative activity against four different tumor cell lines is reported. Keywords: C-2 substituted adamantane, 4-(2-adamantyl)phenylalkylamines, antiproliferative activity. INTRODUCTION Compounds with adamantane core skeletons have been of interest to medicinal chemists since the early1960s. The adamantyl group is present in seven registered therapeutic agents currently in clinical use, and in many other agents in clinical development for the treatment of conditions such as iron overload disease, tuberculosis, malaria and cancer [1-4]. In many cases, the adamantyl group has been found to in- crease the drug-like properties of a lead compound without increasing toxicity. In previous publications [5-7], we re- ported the synthesis and the antiproliferative activity of the diaryladamantane alkylamines of type I and II (Fig. 1). We previously observed that alkylamines I and II have significant cytotoxicity in various cancer cell lines, which *Address correspondence to these authors at the School of Health Sciences, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, National and Kapodistrian University of Athens, Panepistimioupoli-Zografou, 157 84 Athens, Greece, and Institute of Pharmaceutical Science, King’s College London, Britannia House, 7 Trinity Street, London SE1 1DB, UK; Tel: 00302107274808; Fax: 00302107274747; E-mail: papanastasiou@pharm.uoa.gr prompted us to investigate the antiproliferative activity of the novel 4-(2-adamantyl)arylalkylamines of type 1-4 (Fig. 2) to elucidate the role of the two benzene rings and the C1- substitution of the adamantane ring in the cytotoxicity of the molecules. Analogues 1-4 were tested against four different tumor cell lines and found to be cytotoxic with low micro- molar IC 50 values (Table 1). RESULTS AND DISCUSSION Chemistry Synthesis of the 4-(2-adamantyl)anilines 1a-d was achieved from the bromoanilines 5a-c by the reaction se- quence shown in Scheme 1. The bromoanilines 5a-c were prepared from the commer- cially available 1-(4-bromophenyl)piperazine hydrochloride (5e) (Fig. 3), which was treated with a formaldehyde solu- tion under modified Borch-Hassid reaction conditions fol- lowed by reduction of the intermediate methyleneimmonium cation with sodium cyanoborohydride to give 5a [8]. The 4- isopropyl (5b) and 4-cyclohexyl (5c) piperazines were pre- C CH 2 CH 2 CH 2 N X X' R R I CH 2 CH II n X, X' : H, CH 3 , CH 3 O, F N R R : N N R N R R : N N R n : 0, 1, 2, 3 or N or N N R R Fig. (1). Diaryladamantanealkylamines I and II. 1875-6255/15 $58.00+.00 © 2015 Bentham Science Publishers