Research Papers:

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

Anastasia De Luca _, Dante Rotili, Debora Carpanese, Alessia Lenoci, Laura Calderan, Manuel Scimeca, Antonello Mai, Elena Bonanno, Antonio Rosato, Cristina Geroni, Luigi Quintieri and Anna Maria Caccuri

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Oncotarget. 2015; 6:4126-4143. https://doi.org/10.18632/oncotarget.2798

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Anastasia De Luca1, Dante Rotili2, Debora Carpanese3, Alessia Lenoci2, Laura Calderan4, Manuel Scimeca5,6, Antonello Mai2,7, Elena Bonanno5,6, Antonio Rosato3,8, Cristina Geroni9, Luigi Quintieri4, Anna Maria Caccuri1,10

1The NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata, 00133 Rome, Italy

2Department of Drug Chemistry and Technologies, “Sapienza” University, 00185 Rome, Italy

3Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy

4Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy

5Department of Biomedicine and Prevention, University of Tor Vergata, 00133 Rome, Italy

6TMALab s.r.l., Spin-off of University of Tor Vergata, 00133 Rome, Italy

7Pasteur Institute, Cenci-Bolognetti Foundation, “Sapienza” University, 00185 Rome, Italy

8Istituto Oncologico Veneto IRCCS, 35128 Padova, Italy

9On-kòs Pharma Consulting, 20100 Milan, Italy

10Department of Experimental Medicine and Surgery, University of Tor Vergata, 00133 Rome, Italy

Correspondence to:

Anna Maria Caccuri, e-mail: [email protected]

Antonio Rosato, e-mail: [email protected]

Antonello Mai, e-mail: [email protected]

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


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 IC50 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.

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