Inhibitory activities against topoisomerase I and II by isoaurostatin derivatives and their structure–activity relationships

Isoaurostatin A (IAS-A) isolated from Thermomonospora alba showed weak inhibition against topoisomerase (topo) I (IC50 = 307 μM). To get more strong inhibition, derivatives of IAS-A were prepared and their structure–activity relationships against topo I and II were investigated. The addition of hydroxyl group on aromatic rings increased the activities, 3-(3,4,5-trihydroxybenzylidene)-5-hydroxy-3H-benzofuran-2-one (IAS-9) showed strong inhibition (IC50 = 3 μM) against topo I. And also, the increasing of hydroxyl group increased growth inhibition against a variety of cancer cells, and IAS-9 showed most potent inhibition. Unlike camptothecin and etoposide, IAS-9 neither stabilized DNA–topo cleavable complex nor intercalated into DNA, and it inhibited topo I and II noncompetitively. The inhibitory activities also increased by opening of lactone ring in the molecule of IAS-9.