2. Academic Validation
  3. Synthesis and structure--activity relationship of new cytotoxic agents targeting human glutathione-S-transferases

Synthesis and structure--activity relationship of new cytotoxic agents targeting human glutathione-S-transferases

  • Eur J Med Chem. 2015 Jan 7:89:156-71. doi: 10.1016/j.ejmech.2014.10.033.
Dante Rotili 1,  Anastasia De Luca 2,  Domenico Tarantino 1,  Silvia Pezzola 2,  Mariantonietta Forgione 1,  Blasco Morozzo Della Rocca 3,  Mattia Falconi 3,  Antonello Mai 4,  Anna Maria Caccuri 5
Affiliations

Affiliations

  • 1 Department of Drug Chemistry and Technologies, "Sapienza" University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
  • 2 NAST Centre for Nanoscience & Nanotechnology & Innovative Instrumentation, University of Tor Vergata, Viale della Ricerca Scientifica, 00133 Rome, Italy.
  • 3 Department of Biology, University of Tor Vergata, Viale della Ricerca Scientifica, 00133 Rome, Italy.
  • 4 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.
  • 5 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.
PMID: 25462236 DOI: 10.1016/j.ejmech.2014.10.033
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.

Keywords

Glutathione-S-transferase; Nitrobenzoxadiazole; Sigma-complex; Suicide inhibitor; Water solubility.

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