title: 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.affiliation: Department of Medicine, Tulane University, Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Lichun
authors.initials: L
authors.lastname: Sun
authors.forename: Natalya I
authors.initials: NI
authors.lastname: Vasilevich
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Fuselier
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Hocart
authors.forename: David H
authors.initials: DH
authors.lastname: Coy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001384:Azetidines / Q000737:chemistry*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D051381:Rats; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C116379:2-azetidinone; D000970:Antineoplastic Agents; D001384:Azetidines; D013267:Stilbenes; C058728:fosbretabulin