Novel piperazinediones as antitumor agents.

Chemical modification of dipeptide mimetic azatyrosine led to a series of piperazinediones. Thirteen piperazinediones were synthesized and tested for their anticancer activity. This series of piperazinedione compounds exhibited potent anticancer activities against human disease-oriented cancer cell lines in NCI60 cancer screening (National Cancer Institute, USA). Among them, four leads (compound 10: , 18: , 21: , and 22: ) exhibited in vitro tumor growth suppression, reducing tumor cell growth to 45.7%- 56.3%, and exhibited broad-spectrum activities. Compound 18: , with 50% cancer cell growth inhibition (GI50) <10 nM in 45 cell lines from the NCI, was selected as the lead for further mechanism of action studies. The mechanism of action was predicted by the COMPARE algorithm and confirmed by experiments as inhibition of tubulin polymerization which inhibits the formation of microtubules. Copyright