A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts

Abstract

// Anastasia De Luca 1 , Dante Rotili 2 , Debora Carpanese 3 , Alessia Lenoci 2 , Laura Calderan 4 , Manuel Scimeca 5, 6 , Antonello Mai 2, 7 , Elena Bonanno 5, 6 , Antonio Rosato 3, 8 , Cristina Geroni 9 , Luigi Quintieri 4 , Anna Maria Caccuri 1, 10 1 The NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata, 00133 Rome, Italy 2 Department of Drug Chemistry and Technologies, “Sapienza” University, 00185 Rome, Italy 3 Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy 4 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy 5 Department of Biomedicine and Prevention, University of Tor Vergata, 00133 Rome, Italy 6 TMALab s.r.l., Spin-off of University of Tor Vergata, 00133 Rome, Italy 7 Pasteur Institute, Cenci-Bolognetti Foundation, “Sapienza” University, 00185 Rome, Italy 8 Istituto Oncologico Veneto IRCCS, 35128 Padova, Italy 9 On-kòs Pharma Consulting, 20100 Milan, Italy 10 Department of Experimental Medicine and Surgery, University of Tor Vergata, 00133 Rome, Italy Correspondence to: Anna Maria Caccuri, e-mail: caccuri@uniroma2.it Antonio Rosato, e-mail: antonio.rosato@unipd.it Antonello Mai, e-mail: antonello.mai@uniroma1.it Keywords: Glutathione Transferase P1-1, c-Jun N-terminal Kinase, 6-((7-nitrobenzo[c][1,2,5]oxadiazoles, Human Melanoma Xenografts Abbreviations: 2-(2-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)ethoxy)ethan-1-ol, MC3165; 2-(2-(2-((7-nitrobenzo[c][1,2,5] oxadiazol-4-yl)thio)ethoxy)ethoxy)ethanol, MC3181; 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol, NBDHEX; glutathione transferase, GST; temozolomide, TMZ Received: August 22, 2014      Accepted: November 20, 2014      Published: February 13, 2015 ABSTRACT We designed and synthesized two novel nitrobenzoxadiazole (NBD) analogues of the anticancer agent 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX). The new compounds, namely MC3165 and MC3181, bear one and two oxygen atoms within the hydroxy-containing alkyl chain at the C4 position of the NBD scaffold, respectively. This insertion did not alter the chemical reactivity with reduced glutathione, while it conferred a remarkable increase in water solubility. MC3181 was more selective than NBDHEX towards the target protein, glutathione transferase P1-1, and highly effective in vitro against a panel of human melanoma cell lines, with IC 50 in the submicromolar-low micromolar range. Interestingly, the cellular response to MC3181 was cell-type-specific; the compound triggered a JNK-dependent apoptosis in the BRAF-V600E-mutated A375 cells, while it induced morphological changes together with an increase in melanogenesis in BRAF wild-type SK23-MEL cells. MC3181 exhibited a remarkable therapeutic activity against BRAF-V600E-mutant xenografts, both after intravenous and oral administration. Outstandingly, no treatment-related signs of toxicity were observed both in healthy and tumor-bearing mice after single and repeated administrations. Taken together, these results indicate that MC3181 may represent a potential novel therapeutic opportunity for BRAF-mutated human melanoma, while being safe and water-soluble and thus overcoming all the critical aspects of NBDHEX in vivo .