P. Krishnan et Kf. Bastow, The 9-position in berberine analogs is an important determinant of DNA topoisomerase II inhibition, ANTI-CAN DR, 15(4), 2000, pp. 255-264
A current model suggests that the intercalative and minor groove binding co
mponents of protoberberines and related compounds are important for DNA top
oisomerase I and/or II inhibition. The significance of the 9-substituent in
berberine on drug-topoisomerase II interactions is reported here and is ba
sed on a comparison of 9-ethoxycarbonyl berberine (compound 1), 9-N,N-dimet
hylcarbamoyl berberine (compound 2) and 12-bromo berberine (methoxy group a
t 9-position; compound 3) as enzyme inhibitors, Compound 1 selectively inhi
bited topoisomerase II and stabilized cleavage complexes predominantly at u
nique sites and some background sites (depending on the concentration). Thi
s agent also allowed partial dissociation of enzyme from the DNA in the abs
ence of religation, indicating unique interactions between 1, enzyme and DN
A in the ternary complexes. Compound 2, which had similar DNA binding prope
rties to 1, was not a topoisomerase II poison in the tested concentration r
ange. In contrast, compound 3 was a stronger DNA binding agent but a much w
eaker enzyme poison both in vitro and in cell-based assays. The results sho
w that the proposed drug domain for DNA intercalation is not a major determ
inant of enzyme inhibition for simple berberine analogs. Rather, the 9-subs
tituent within the domain has a major influence, presumably by facilitating
drug interaction with enzyme and/or enzyme-DNA complexes.