The 9-position in berberine analogs is an important determinant of DNA topoisomerase II inhibition

Citation
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
Citations number
24
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ANTI-CANCER DRUG DESIGN
ISSN journal
0266-9536 → ACNP
Volume
15
Issue
4
Year of publication
2000
Pages
255 - 264
Database
ISI
SICI code
0266-9536(200008)15:4<255:T9IBAI>2.0.ZU;2-G
Abstract
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.