title: A novel orally active water-soluble inhibitor of human glutathione transferase exerts a potent and selective antitumor activity against human melanoma xenografts.
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 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.
authors.affiliation: The NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata, 00133 Rome, Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Department of Drug Chemistry and Technologies, "Sapienza" University, 00185 Rome, Italy.
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Carpanese
authors.affiliation: Department of Drug Chemistry and Technologies, "Sapienza" University, 00185 Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Lenoci
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Calderan
authors.affiliation: Department of Biomedicine and Prevention, University of Tor Vergata, 00133 Rome, Italy.|TMALab s.r.l., Spin-off of University of Tor Vergata, 00133 Rome, Italy.
authors.forename: Manuel
authors.initials: M
authors.lastname: Scimeca
authors.affiliation: Department of Drug Chemistry and Technologies, "Sapienza" University, 00185 Rome, Italy.|Pasteur Institute, Cenci-Bolognetti Foundation, "Sapienza" University, 00185 Rome, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.affiliation: Department of Biomedicine and Prevention, University of Tor Vergata, 00133 Rome, Italy.|TMALab s.r.l., Spin-off of University of Tor Vergata, 00133 Rome, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonanno
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.|Istituto Oncologico Veneto IRCCS, 35128 Padova, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Rosato
authors.affiliation: On-kòs Pharma Consulting, 20100 Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Geroni
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131 Padova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Quintieri
authors.affiliation: The NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata, 00133 Rome, Italy.|Department of Experimental Medicine and Surgery, University of Tor Vergata, 00133 Rome, Italy.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Caccuri
mesh_terms: D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051379:Mice; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D004791:Enzyme Inhibitors; D010069:Oxadiazoles; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi