Topoisomerase II inhibition by aporphine alkaloids

The aporphine alkaloids (+)-dicentrine and (+)-bulbocapnine are non-planar molecules lacking features normally associated with DNA binding by intercal ation or minor groove binding. Surprisingly, dicentrine showed significant activity as a topoisomerase II (EC 5.99.1.3) inhibitor and also was active in a DNA unwinding assay. The DNA unwinding suggests DNA intercalation, whi ch could explain the inhibition of topoisomerase II. Bulbocapnine, which di ffers from dicentrine only by the presence of a hydroxyl group at position 11 and the absence of a methoxyl group at position 9, was inactive in all a ssays. Molecular modeling showed that dicentrine can attain a relatively pl anar conformation, whereas bulbocapnine cannot, due to steric interaction b etween the Il-hydroxyl group and an oxygen of the methylenedioxy ring. Thes e observations suggest that dicentrine is an "adaptive" DNA intercalator, w hich can bind DNA only by adopting a somewhat strained planar conformation. The requirement uf a suboptimal conformation to achieve DNA binding appear s to make dicentrine a weaker topoisomerase II inhibitor than the very plan ar oxoaporphine alkaloid liriodenine. These results suggest that it may be possible to modulate DNA binding and biologic activity of drugs by modifica tions affecting their ability to adopt planar conformations. (C) 1999 Elsev ier Science Inc.