The aporphine alkaloids (+)-dicentrine and (+)-bulbocapnine are non-planar 
molecules lacking features normally associated with DNA binding by intercalation 
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, which could 
explain the inhibition of topoisomerase II. Bulbocapnine, which differs 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 assays. Molecular 
modeling showed that dicentrine can attain a relatively planar conformation, 
whereas bulbocapnine cannot, due to steric interaction between the 11-hydroxyl 
group and an oxygen of the methylenedioxy ring. These observations suggest that 
dicentrine is an "adaptive" DNA intercalator, which can bind DNA only by 
adopting a somewhat strained planar conformation. The requirement of a 
suboptimal conformation to achieve DNA binding appears to make dicentrine a 
weaker topoisomerase II inhibitor than the very planar oxoaporphine alkaloid 
liriodenine. These results suggest that it may be possible to modulate DNA 
binding and biologic activity of drugs by modifications affecting their ability 
to adopt planar conformations.