Synthesis, Biological Evaluation, and Structure−Activity Relationships of Dithiolethiones as Inducers of Cytoprotective Phase 2 Enzymes

Abstract

Dithiolethiones are a family of promising cancer chemopreventive agents, and induction of Phase 2 enzymes is key to their chemopreventive activities. Two dithiolethiones have been evaluated in humans for cancer prevention. While some chemopreventive activities were detected in several human studies, potential side effects are a concern. Herein, we report structure-activity relationships of 25 dithiolethiones. Several compounds show exceedingly potent and bladder specific activity in Phase 2 enzyme induction. Structural features responsible for such activity, as well as those inhibiting the activity, are discussed. Moreover, the compounds activate and depend on Nrf2 for their inductive activities. Nrf2 is a major transcriptional stimulator of cytoprotective genes and is critical for cancer prevention. Thus, several new dithiolethiones that are highly promising for bladder cancer prevention have been identified. Because the compounds act specifically in the bladder, the likelihood of potential systemic toxicity may be low.

A dietary isothiocyanate-enriched moringa (Moringa oleifera) seed extract improves glucose tolerance in a high-fat-diet mouse model and modulates the gut microbiome

“…Another study has shown that MIC-1 (also called moringin) significantly increases the nuclear expression of Nrf2 in LPS-stimulated macrophages (Rajan et al, 2016), supporting the direct regulation of Nrf2 by MIC-1. In this study, MSE significantly regulated the gene expression of iNOS and NQO1 in vivo , which are associated with chronic inflammation, oxidative stress, and obesity-induced insulin resistance in mice (Fujimoto et al, 2005; Munday et al, 2010; Shinozaki et al, 2011), supporting the role of MIC-1 as the primary bioactive component of MSE and the mechanism by which MSE improved the glucose tolerance and overall metabolic health of the mice.…”

Hydrolysis‐Sensitive Dithiolethione Prodrug Micelles

“…PAM-PIleOtBu block copolymer (12). 400 mg (25 mmol) of (10), 224 mg (1.25 mmol) of EPHP and 2.05 mg (12.5 mmol) of AIBN were dissolved in 2.5 mL of DMF.…”

“…Despite their potential in cancer therapy and prevention, clinical trials of dithiolethiones such as Oltipraz resulted in a questionable efficacy and significant side effects . Toward improved chemopreventive effects, considerable efforts have been made to synthesize different dithiolethione derivatives that are more effective in inducing phase II enzymes . However, potential problems would be unfavorable pharmacokinetics due to the rapid spreading throughout the body and lack of tissue specificity, which are often associated with the use of low‐molecular weight drugs.…”

Anethole Dithiolethione Increases Glutathione in Kidney by Inhibiting γ-Glutamyltranspeptidase: Biochemical Interpretation and Pharmacological Consequences

“…GSH is the main cellular antioxidant and works by donating reducing equivalents and conjugating with electrophiles via GST catalysis in phase II detoxification reactions; therefore, its role is fundamental in the elimination of xenobiotics and reactive oxygen species (ROS) [ 6 , 7 ]. It was also reported that ADT can activate Nrf2, which is a major transcriptional stimulator of antioxidant and cytoprotective genes and is critical for cancer prevention [ 8 ].…”