Examination of the 1,4-disubstituted azetidinone ring system as a template for combretastatin A-4 conformationally restricted analogue design |
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Authors: | Sun Lichun Vasilevich Natalya I Fuselier Joseph A Hocart Simon J Coy David H |
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Institution: | Department of Medicine, Tulane University, Health Sciences Center, New Orleans, LA 70112, USA. |
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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. |
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