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

• Published in: Bioorganic & medicinal chemistry letters Vol. 14; no. 9; pp. 2041 - 2046
• Main Authors: SUN, Lichun, VASILEVICH, Natalya I, FUSELIER, Joseph A, HOCART, Simon J, COY, David H
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier 03-05-2004
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Azetidines - chemistry; Biological and medical sciences; Cell Line, Tumor; General aspects; Humans; Medical sciences; Mice; Mice, Nude; Models, Molecular; Pharmacology. Drug treatments; Rats; Stilbenes - chemical synthesis; Stilbenes - chemistry; Stilbenes - pharmacology; Antineoplastic agent; Cell proliferation; Lactam; Cytotoxicity; Neuroblastoma; Stereoselectivity; Structure activity relation; Molecular model; Inhibition; Pancreas; Chemical synthesis; Antimitotic; Tumor cell; Human; Molecular rigidity; Four membered ring; Rodentia; Antitubulin; Steric hindrance; Aniline derivatives; Malignant tumor; In vitro; In vivo; Vertebrata; Mammalia; Cell line; Staudinger reaction; Mouse; Animal; Azetidine derivatives; Aromatic amine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.02.050

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.