Replacement of a quinone by a 5-O-acetylhydroquinone abolishes the accidental necrosis inducing effect while preserving the apoptosis-inducing effect of renieramycin M on lung cancer cells.

Abstract

Renieramycin M (1), a bistetrahydroisoquinolinequinone alkaloid isolated from the marine sponge Xestospongia sp., has been reported to possess promising anticancer effects. However, its accidental necrosis inducing effect has limited further development due to concerns of unwanted toxicity. The presence of two quinone moieties in its structure was demonstrated to induce accidental necrosis and increase reactive oxygen species (ROS) levels. Therefore, one quinone of 1 was modified to produce the 5-O-acetylated hydroquinone derivative (2), and 2 dramatically reduced the accidental necrosis inducing effect while preserving the apoptosis-inducing effect of parent 1 on lung cancer H23 cells. Addition of the antioxidant N-acetylcysteine suppressed the accidental necrosis mediated by 1, suggesting that its accidental necrosis inducing effect was ROS-dependent. The fluorescent probe dihydroethidium revealed that the accidental necrosis mediated by 1 was due to its ability to generate intracellular superoxide anions. Interestingly, the remaining quinone in 2 was required for its cytotoxicity, as the 5,8,15,18-O-tetraacetylated bishydroquinone derivative (3) exhibited weak cytotoxicity compared to 1 and 2. The present study demonstrates a simple way to eliminate the undesired accidental necrosis inducing effect of substances that may be developed as improved anticancer drug candidates.

• Authors: Thaniwan Cheun-Arom, Pithi Chanvorachote, Natchanun Sirimangkalakitti, Taksina Chuanasa, Naoki Saito, Ikuro Abe, Khanit Suwanborirux
• Journal: Journal of natural products (J Nat Prod) Vol. 76 Issue 8 Pg. 1468-74 (Aug 23 2013) ISSN: 1520-6025 [Electronic] United States
• PMID: 23876104 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-O-acetylhydroquinone
• Alkaloids
• Antineoplastic Agents
• Hydroquinones
• Tetrahydroisoquinolines
• Tumor Suppressor Protein p53
• renieramycin M
• Acetylcysteine

Topics

• Acetylcysteine (chemistry, pharmacology)
• Alkaloids (chemistry, pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Humans
• Hydroquinones (chemistry)
• Lung Neoplasms (drug therapy)
• Molecular Structure
• Necrosis (drug therapy)
• Structure-Activity Relationship
• Tetrahydroisoquinolines (chemistry, pharmacology)
• Tumor Suppressor Protein p53 (drug effects)