Synthesis and anticancer activity of 4-aza-daurinol derivatives.

Daurinol, a natural aryl naphthalene lactone, has been reported to have antiproliferative activity against various cell lines, and has also been shown to be efficacious in an in vivo xenograft mouse model. In this study, we tried to discover a new scaffold that enables both rapid structure-activity relationship study of daurinol and scalable synthesis of active compounds. 4-Aza-daurinol, a bioisosterism-based scaffold of daurinol, was designed and 17 analogues were synthesized and evaluated against five representative cancer cell lines. Among them, the 2,3-dihydrobenzo[b][1,4]dioxinyl derivative was found to be the most potent and showed similar activity and tendency as daurinol.