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

• We present here 39 new analogs of NBDHEX (1), a suicide inhibitor of the GSTs.
• Some of them were 10–100 times more water-soluble than 1.
• Most of them showed higher GSTP1-1 selectivity than 1.
• Compounds 30 and 32 displayed higher toxicity than 1 in osteosarcoma U-2OS cells.

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.

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