New naphthoquinone derivatives against glioma cells Marco Redaelli b , Carla Mucignat-Caretta b , Abdirisak Ahmed Isse d , Armando Gennaro d , Raffaele Pezzani c , Riccardo Pasquale a , Valeria Pavan a , Marco Crisma e , Giovanni Ribaudo a , Giuseppe Zagotto a, * a Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via Marzolo 5, 35131 Padova, Italy b Department of Molecular Medicine, University of Padova, Via Marzolo 3, 35131 Padova, Italy c Department of Medical and Surgical Sciences-Operative Unit of Endocrinology, University of Padova, Via Ospedale 105, 35128 Padova, Italy d Department of Chemical Sciences, University of Padova, Via Marzolo 1, 35131 Padova, Italy e Institute of Biomolecular Chemistry, Padova Unit, CNR, Via Marzolo 1, 35131 Padova, Italy article info Article history: Received 27 October 2014 Received in revised form 14 April 2015 Accepted 17 April 2015 Available online 21 April 2015 Keywords: Glioma Naphtoquinones Redox Temozolomide abstract This work was aimed to the development of a set of new naphtoquinone derivatives that can act against glioma. The compounds were tested in order to find out their ability to inhibit the growth of glioma cells, and the results of these assays were correlated with electrochemical analysis and NMR-based reoxidation kinetic studies, suggesting that a redox mechanism underlies and may explain the observed biological behavior. In addition to a full description of the synthetic pathways, electrochemistry, NMR and single crystal X-ray diffraction data are provided. © 2015 Elsevier Masson SAS. All rights reserved. 1. Introduction Gliomas are tumors most frequently affecting the central ner- vous system (CNS). According to the gliomas classification provided by the World Health Organization [1], the most malignant grade is glioblastoma (Grade IV, GB). The current therapeutic approach that FDA approved consists in neurosurgical resection, followed by chemotherapy with temozolomide (TMZ) in combination with radiotherapy, though only 26% of treated patients reached 2 years of survival [2]. Despite all the recent advances in neurosurgery [3] and chemotherapy [4], glioblastoma presents highly invasive pattern and recurs in 90% of cases [5]. Many attempts to define the specific biomolecular characteristics of these complex and variable tumors have been carried out during the last decades [6], though no promising discoveries successfully migrated from the bench to the clinic [7]. At present, investigation on modulation of specific targets and consequent effects on glioma cells is one of the most concrete approaches towards a better understanding of the mechanism involved in gliomas malignancy. Alternative therapeutic approaches based on novel compounds and/or discovery of inter- esting biological activities of known compounds are therefore necessary. Recently, indeed, the interest towards natural derivatives developed and naphthoquinones, among the others, continuously captivated biological interest. In this connection, the applications of both natural (as in the case of 3-hydroxy-5-methoxy-2- methylbenzoquinone and heliquinone, from Sterculiaceae family) [8] and semi-synthetic derivatives have been widely investigated. For instance it has been reported that water-soluble naph- thoquinone derivatives e i.e. their conjugated with carbohydrates e show cytotoxic activity in JB6 P þ Cl41 cells [9], while other 1,4- naphthoquinones have been synthesized and evaluated for many other purpouses, such as their trypanocidal activity [10]. Juglone is a natural compound deriving from the Juglandaceae family, particularly Juglans nigra, whose toxic and growth-stunting effects are well known [11]. While Juglone was reported to induce generic oxidative stress in both healthy cells and cancer cell lines [12], we previously highlited the cytotoxic effect of its derivative 1 in inducing apoptotic cell death on human glioma cell lines [13] as a result of a screening on our in-house database. Starting from the discovery of this promising lead, the synthesis of novel naph- thoquinone derivatives stems out with the aim of describing and * Corresponding author. E-mail address: giuseppe.zagotto@unipd.it (G. Zagotto). 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.2015.04.039 0223-5234/© 2015 Elsevier Masson SAS. All rights reserved. European Journal of Medicinal Chemistry 96 (2015) 458e466