Oxathiolene oxides: a novel family of compounds that induce ferritin, glutathione S-transferase, and other proteins of the phase II response

Abstract

Compounds that induce the synthesis of cytoprotective phase II enzymes have shown promise as cancer chemopreventive agents. Although chemically diverse, phase II enzyme inducers are capable of participating in Michael reaction chemistry. We have synthesized a novel class of organosulfur compounds, termed oxathiolene oxides (OTEOs). Based on their chemical properties, we hypothesized that these compounds could function as phase II enzyme inducers. Northern blot analysis showed that oxathiolene oxides induce the phase II enzymes glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1 (NQO1), and ferritin H and L mRNA in a concentrationdependent fashion in a normal embryonic mouse liver cell line, BNLCL.2. OTEO-562 (3-cyclohexenyl-4-methyl-1,2-oxathiol-3-ene-2-oxide) was the strongest inducer. Western blot analysis demonstrated that GST-a and ferritin H protein levels were also induced in cells treated with OTEO-562, as was total GST and NQO1 enzyme activity. Further, induction of NQO1 activity by OTEO-562 was equivalent in aromatic hydrocarbon (Ah) receptor wild-type and Ah receptor mutant cell lines, suggesting that oxathiolene oxides activate phase II enzymes by an Ah receptor-independent mechanism. Consistent with this observation, OTEO-562 failed to induce cytochrome P450 1A1 mRNA. These results suggest that oxathiolene oxides may merit further investigation as candidate chemopreventive agents. #

Preparation of Disubstituted Phenyl Propargyl Alcohols, their Use in Oxathiolene Oxide Synthesis, and Evaluation of the Oxathiolene Oxide Products as Anticarcinogenic Enzyme Inducers

“…We had already established that the oxathiolene oxide nucleus was a promising phase 2 inducer back in 2003, but the synthetic chemistry used to prepare the initial set of four test compounds was too cumbersome [18]. Hence, the simple synthetic route to these compounds outlined above was initially developed for monosubstituted aromatic substrates in 2005 [19].…”

“…Several compounds were prepared using the transition-metal mediated [3 + 2] cycloaddition chemistry described above and then were shown to elevate mRNA levels of glutathione S-transferase (GST), quinone oxidoreductase (NQO1), and ferritin H and L expression in a normal murine liver cell line, BNLCL.2 [18]. Having verified that compounds containing the oxathiolene oxide nucleus could be nontoxic, anticarcinogenic enzyme inducers at both the mRNA and protein levels, we wanted to evaluate this class of compounds in more detail.…”

Serum glutathione transferase does not respond to indole-3-carbinol: A pilot study

“…[21][22][23][24] The enzymes do this primarily by attaching a glutathione molecule to electrophiles, making them water-soluble, which facilitates urinary or biliary excretion. 19,[25][26][27] This is the first step in the formation of mercapturic acids, a pathway which results in the elimination of potentially toxic compounds from the body. 19,[28][29][30] Within mammalian cells, at least five different isoenzymes of glutathione transferases have been discovered.…”

Mechanisms of iron metabolism in Caenorhabditis elegans

“…However, mammalian ferritin is transcriptionally activated by oxidative stress (Thimmulappa et al, 2002; Pietsch et al, 2003a,b; Hintze and Theil, 2005) and repressed by oncogenes, providing a mechanism to sequester iron during stress and to increase iron availability during cell proliferation (Tsuji et al, 1993, 1995; Wu et al, 1999). Similarly, several studies have shown that ferritin depletion stimulates cell proliferation by increasing available iron, whereas sequestration of iron by ferritin overexpression slows cell proliferation (Cozzi et al, 2000; Kakhlon et al, 2001; Cozzi et al, 2004; Baldi et al, 2005).…”