2-Amino and 2′-aminocombretastatin derivatives as potent antimitotic agents

A novel series of 2-amino and 2′-aminocombretastatin derivatives were synthesized and evaluated for antitumor activity. Several compounds had excellent antiproliferative activity as inhibitors of tubulin polymerization. Compounds 11, 20, and 21 with IC₅₀ values of 1.6, 1.7, and 1.8 μM, respectively, exhibited more potent inhibition of tubulin polymerization than colchicine and approximately as active as combretastatin A-4. They also displayed antiproliferative activity with an IC₅₀ values ranging from 11 to 44 nM in a variety of human cell lines from different organs. Structure activity relationship information suggests that the NH₂ substituent at the 2-position of either ring A or ring B in combretastatin molecular skeleton may play an important role in the bioactivity of this series of compounds.