Alkynol natural products target ALDH2 in cancer cells by irreversible binding to the active site.

Abstract

Falcarinol and stipudiol are natural products with potent anti-cancer activity found in several vegetables. Here, we use a chemical proteomic strategy to identify ALDH2 as a molecular target of falcarinol in cancer cells and confirm enzyme inhibition via covalent alkylation of the active site. Furthermore, the synthesis of stipudiol led to the observation that ALDH2 exhibits preference for alkynol-based binders. Inhibition of ALDH2 impairs detoxification of reactive aldehydes and limits oxidative stress response, two crucial pathways for cellular viability.

• Authors: Wolfgang Heydenreuter, Elena Kunold, Stephan A Sieber
• Journal: Chemical communications (Cambridge, England) (Chem Commun (Camb)) Vol. 51 Issue 87 Pg. 15784-7 (Nov 11 2015) ISSN: 1364-548X [Electronic] England
• PMID: 26365706 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Alkynes
• Antineoplastic Agents
• Diynes
• Enzyme Inhibitors
• Fatty Alcohols
• Recombinant Proteins
• stipudiol
• falcarinol
• ALDH2 protein, human
• Aldehyde Dehydrogenase
• Aldehyde Dehydrogenase, Mitochondrial
• Cysteine

Topics

• Aldehyde Dehydrogenase (antagonists & inhibitors, chemistry)
• Aldehyde Dehydrogenase, Mitochondrial
• Alkynes (chemical synthesis, pharmacology)
• Antineoplastic Agents (chemical synthesis, pharmacology)
• Catalytic Domain
• Click Chemistry
• Cysteine (chemistry)
• Diynes (chemical synthesis, pharmacology)
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• Fatty Alcohols (chemical synthesis, pharmacology)
• Hep G2 Cells
• Humans
• Kinetics
• Recombinant Proteins (chemistry)