Synthesis and biological evaluation of substituted 2-benzoylpyridine thiosemicarbazones: novel structure-activity relationships underpinning their anti-proliferative and chelation efficacy.

Abstract

The 2-benzoylpyridine thiosemicarbazone (BpT) chelators demonstrate potent anti-proliferative effects against tumor cells. To understand their structure-activity relationships, BpT analogues incorporating electron-donating substituents on the pyridine and phenyl rings of the BpT scaffold were designed and represent the first attempts to modify the pyridine ring of these thiosemicarbazones. Eight analogues showed significantly (p <0.001) greater anti-proliferative activity than the 'gold-standard' chelator, desferrioxamine. Structure-activity analysis revealed that mono- or di-methoxy substitution at the phenyl ring resulted in lower anti-proliferative activity, while methoxy substitutions at the phenyl ring enhanced iron chelation efficacy. These important findings facilitate the design of thiosemicarbazones with greater anti-tumor activity.

• Authors: Adeline Y Lukmantara, Danuta S Kalinowski, Naresh Kumar, Des R Richardson
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 4 Pg. 967-74 (Feb 15 2013) ISSN: 1464-3405 [Electronic] England
• PMID: 23312948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Benzoates
• Chelating Agents
• Iron Chelating Agents
• Pyridines
• Thiosemicarbazones

Topics

• Animals
• Benzoates (chemical synthesis, pharmacology)
• Cell Growth Processes (drug effects)
• Chelating Agents (chemical synthesis, pharmacology)
• Crystallography, X-Ray
• Humans
• Iron Chelating Agents (chemical synthesis, pharmacology)
• Mice
• Pyridines (chemical synthesis, pharmacology)
• Structure-Activity Relationship
• Thiosemicarbazones (chemical synthesis, pharmacology)