The 9-position in berberine analogs is an important determinant of DNA topoisomerase II inhibition.
A current model suggests that the intercalative and minor groove binding components of protoberberines and related compounds are important for DNA topoisomerase I and/or II inhibition. The significance of the 9-substituent in berberine on drug-topoisomerase II interactions is reported here and is based on a comparison of 9-ethoxycarbonyl berberine (compound 1), 9-N,N-dimethylcarbamoyl berberine (compound 2) and 12-bromo berberine (methoxy group at 9-position; compound 3) as enzyme inhibitors. Compound 1 selectively inhibited topoisomerase II and stabilized cleavage complexes predominantly at unique sites and some background sites (depending on the concentration). This agent also allowed partial dissociation of enzyme from the DNA in the absence of religation, indicating unique interactions between 1, enzyme and DNA in the ternary complexes. Compound 2, which had similar DNA binding properties to 1, was not a topoisomerase II poison in the tested concentration range. In contrast, compound 3 was a stronger DNA binding agent but a much weaker enzyme poison both in vitro and in cell-based assays. The results show that the proposed drug domain for DNA intercalation is not a major determinant of enzyme inhibition for simple berberine analogs. Rather, the 9-substituent within the domain has a major influence, presumably by facilitating drug interaction with enzyme and/or enzyme-DNA complexes.
Krishnan
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P
Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill 27599, USA.
Bastow
K F
KF
D001599:Berberine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004278:DNA, Superhelical / Q000737:chemistry / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006358:Hot Temperature; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000494:pharmacology; D007624:KB Cells; D007700:Kinetics; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D059005:Topoisomerase II Inhibitors; D001599:Berberine; D004250:DNA Topoisomerases, Type II