Original article Haloperidol metabolite II prodrug: Asymmetric synthesis and biological evaluation on rat C6 glioma cells Piera Sozio a, 1 , Jole Fiorito b, 1 , Viviana Di Giacomo a, 1 , Antonio Di Stefano a , Lisa Marinelli a , Ivana Cacciatore a , Amelia Cataldi a , Stephanie Pacella a , Hasan Turkez c , Carmela Parenti d , Antonio Rescifina d , Agostino Marrazzo d, * a Dipartimento di Farmacia, Universit a degli Studi di Chieti Gabriele D'Annunzio, Via dei Vestini 31, 66100 Chieti, Italy b Department of Pathology and Cell Biology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, 630 W 168th St., New York, NY 10032, USA c Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, 25240 Erzurum, Turkey d Dipartimento di Scienze del Farmaco, Universit a degli Studi di Catania, Viale Andrea Doria 6, 95125 Catania, Italy article info Article history: Received 1 February 2014 Received in revised form 4 November 2014 Accepted 5 November 2014 Available online 6 November 2014 Keywords: Glioma HDAC Sigma receptors Inhibitors Medicinal chemistry abstract In a previous work we reported the antiproliferative effects of (±)-MRJF4, a novel haloperidol metabolite II (HP-mII) (a sigma-1 antagonist and sigma-2 agonist) prodrug, obtained through conjugation to 4- phenylbutyric acid (PhBA) [a histone deacetylase inhibitor (HDACi)] via an ester bond. As a continua- tion of this work, here we report the asymmetric synthesis of compounds (R)-(þ)-MRJF4 and (S)- ()-MRJF4 and the evaluation of their biological activity on rat C6 glioma cells, derived from glioblas- toma multiforme (GBM), which is the most common and deadliest central nervous system (CNS) invasive malignancy. Favourable physicochemical properties, high permeability in the parallel artificial membrane permeability assay (PAMPA), good enzymatic and chemical stability, in vivo anticancer activity, associ- ated with the capacity to reduce cell viability and to increase cell death by apoptosis, render compound (R)-(þ)-MRJF4 a promising candidate for the development of a useful therapeutic for gliomas therapy. © 2014 Elsevier Masson SAS. All rights reserved. 1. Introduction Malignant gliomas are the most common types of primary brain tumours and remain one of the deadliest forms of brain cancer in humans. New efficient chemotherapeutics for such malignant gli- omas treatment were developed over the years and many are still under investigation. There is evidence that the best treatment consists of surgical resection followed by chemotherapy; combi- nation of prednisone, lomustine and vincristine could increase survival rate in children with gliomas, whereas temozolomide could prolong the survival of adult patients [1]. Despite the fact that different treatments are available, the prognosis remains poor, particularly for glioblastoma multiforme (GBM), which has survival rate of less than 3% at 3 years [2,3]. To date, new anticancer compounds that are currently in clinical trial for gliomas are inspired from existing molecules selected for other types of cancer. Mainly, these molecules target intracellular signalling pathways relative to either growth or angiogenesis and were efficient in preclinical models of gliomas [1]. Decreasing the level of migration in various cancer cell types, including GBM, commonly restores a certain level of sensitivity to apoptosis and/or cytotoxic drugs [4]. Furthermore, was reported that glioma cells tend to display an overexpression of sigma (s) receptors [5]. In this regard, N-(1-benzylpiperidin-4-yl)-4-iodobenzamide (4-IBP), a se- lective s 1 agonist, demonstrated significant anti-migratory in vitro activity in different analysed cancer cell lines, including the highly motile human U373-MG GBM cell line [4,6e8]. On the other hand, also haloperidol, a potent s 1 antagonist used as anti-psychotic drug, showed antiproliferative effects against glioma cells at low con- centration (5 mM) [9]. Literature data reported that the prodrug approach was widely used to improve the delivery of anticancer drugs (chlorambucil, camptothecin, paclitaxel, doxorubicin, and vinblastine) [10]. In our previous work, using this strategy, we synthesized (±)-MRJF4, a novel ester prodrug of haloperidol metabolite II (HP-mII) for the treatment of prostate cancer [10] (Fig. 1). HP-mII e endowed with s 1 antagonist and s 2 agonist properties e resulted to be more lipophilic than the parent drug following the esterification with * Corresponding author. E-mail address: marrazzo@unict.it (A. Marrazzo). 1 These authors contribute equally to this work. Contents lists available at ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech http://dx.doi.org/10.1016/j.ejmech.2014.11.012 0223-5234/© 2014 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 90 (2015) 1e9