Topoisomerase II inhibition by aporphine alkaloids.
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.
Woo
S H
SH
Department of Radiology, Division of Radiobiology; Department of Molecular Virology, Immunology, and Human Genetics; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
Sun
N J
NJ
Cassady
J M
JM
Snapka
R M
RM
D000818:Animals; D001060:Aporphines / Q000737:chemistry / Q000494:pharmacology*; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D015195:Drug Design; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D001060:Aporphines; D007364:Intercalating Agents; D059005:Topoisomerase II Inhibitors; D004247:DNA; D004250:DNA Topoisomerases, Type II; C067342:dicentrine