Synthesis, biological evaluation, and structure-activity relationships of dithiolethiones as inducers of cytoprotective phase 2 enzymes.
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.
Munday
Rex
R
AgResearch, Ruakura Research Centre, Private Bag 3123, Hamilton, New Zealand. rex.munday@agresearch.co.nz
Zhang
Yuesheng
Y
Paonessa
Joseph D
JD
Munday
Christine M
CM
Wilkins
Alistair L
AL
Babu
Jacob
J
D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004790:Enzyme Induction; D005260:Female; D055785:Gene Knockdown Techniques; D005982:Glutathione Transferase / Q000096:biosynthesis*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000201:enzymology; D001749:Urinary Bladder Neoplasms / Q000517:prevention & control
D016588:Anticarcinogenic Agents; D051267:NF-E2-Related Factor 2; D013871:Thiones; D013876:Thiophenes; D016660:NAD(P)H Dehydrogenase (Quinone); C507703:NQO1 protein, rat; D005982:Glutathione Transferase; C049325:1,2-dithiol-3-thione