title: Synthesis and structure--activity relationship of new cytotoxic agents targeting human glutathione-S-transferases.
abstract: The 6-((7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)thio)hexan-1-ol (NBDHEX, 1), a "suicide inhibitor" of the glutathione-S-transferase GSTP1-1, showed pro-apoptotic properties in tumor cells, but in vivo studies were limited by poor bioavailability and high affinity towards GSTM2-2, expressed in many non-cancerous tissues. Here we describe the synthesis and biological characterization of new 1 analogs (2-40), in which the hydroxyhexyl portion at the C4-sulfur atom has been replaced with phenyl-containing moieties as well as substituted alkyl chains. Some of the new compounds displayed 10-100 times increased water-solubility (8, 11, 17, 26-28, 34, 35), and most of them showed higher GSTP1-1 selectivity (2-20, 23-26, 31-33, 35) than 1. The presence of a phenyl ring with polar substituents is in general associated, with some exceptions (23, 24) to low cytotoxicity in osteosarcoma U-2OS cells. Differently, some alkyl derivatives possess cytotoxicity comparable (26, 34, 35) or higher (30, 32) than 1. Among the novel compounds, selected ones (26, 27, 34, and 35) deserve further investigation for their anticancer potential.
authors.affiliation: Department of Drug Chemistry and Technologies, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Dante
authors.initials: D
authors.lastname: Rotili
authors.affiliation: NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata, Viale della Ricerca Scientifica, 00133 Rome, Italy.
authors.forename: Anastasia
authors.initials: A
authors.lastname: De Luca
authors.affiliation: Department of Drug Chemistry and Technologies, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Tarantino
authors.affiliation: NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata, Viale della Ricerca Scientifica, 00133 Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pezzola
authors.affiliation: Department of Drug Chemistry and Technologies, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
authors.forename: Mariantonietta
authors.initials: M
authors.lastname: Forgione
authors.affiliation: Department of Biology, University of Tor Vergata, Viale della Ricerca Scientifica, 00133 Rome, Italy.
authors.forename: Blasco
authors.initials: B
authors.lastname: Morozzo Della Rocca
authors.affiliation: Department of Biology, University of Tor Vergata, Viale della Ricerca Scientifica, 00133 Rome, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Falconi
authors.affiliation: Department of Drug Chemistry and Technologies, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy; Pasteur Institute, Cenci Bolognetti Foundation, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy. Electronic address: antonello.mai@uniroma1.it.
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.affiliation: NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata, Viale della Ricerca Scientifica, 00133 Rome, Italy; Department of Experimental Medicine and Surgery, University of Tor Vergata, Viale Oxford 81, 00133 Rome, Italy. Electronic address: caccuri@uniroma2.it.
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Caccuri
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009281:Naphthalenes; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; C571806:orteronel
keywords: Glutathione-S-transferase; Nitrobenzoxadiazole; Sigma-complex; Suicide inhibitor; Water solubility