Examination of the 1,4-disubstituted azetidinone ring system as a template for combretastatin A-4 conformationally restricted analogue design.

Abstract

A series of novel 1,4-diaryl-2-azetidinones was prepared by stereospecific Staudinger reaction as conformationally restricted analogues of combretastatin A-4 because molecular modeling studies suggested close geometric similarities. They were evaluated for cytotoxicity against a number of human tumor and normal cell lines. Strong potencies were observed, with the best compounds exhibiting IC(50)'s of 25-74 nM against human neuroblastoma IMR 32 cell growth and a variety of other cell lines. Compounds inhibited tubulin polymerization with potencies commensurate with their cytotoxic activity and a more soluble anilino-containing analogue was very effective in inhibiting the growth of AR42J rat pancreatic tumors transplanted into in nude mice. Further studies on this interesting group of compounds as anti-cancer agents appear warranted.

• Authors: Lichun Sun, Natalya I Vasilevich, Joseph A Fuselier, Simon J Hocart, David H Coy
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 14 Issue 9 Pg. 2041-6 (May 03 2004) ISSN: 0960-894X [Print] England
• PMID: 15080975 (Publication Type: Journal Article)

Chemical References

• 2-azetidinone
• Antineoplastic Agents
• Azetidines
• Stilbenes
• fosbretabulin

Topics

• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Azetidines (chemistry)
• Cell Line, Tumor
• Humans
• Mice
• Mice, Nude
• Models, Molecular
• Rats
• Stilbenes (chemical synthesis, chemistry, pharmacology)