Inhibition of DNA topoisomerase I by natural and synthetic mono- and dimeric protoberberine alkaloids.
A series of natural (i.e., 1-7) and synthetic (i.e., 8-23) protoberberine alkaloids were evaluated for their inhibitory activities towards DNA topoisomerase I. Both the natural, monomeric protoberberine alkaloids and their mono-modified congeners showed only minor activities. In contrast, most of the dimeric protoberberine alkaloids, especially compounds 12-22, were highly active, with a similar cleavage efficiency as camptothecin (CPT), a well-known, potent topoisomerase-I inhibitor. Thus, these dimeric compounds are promising candidates to be further elaborated as anticancer leads. The mechanism of topoisomerase-I inhibition seems to be dependent on drug concentration for the dimeric protoberberines. At low concentration, they exhibit similar characteristics as CPT. At high concentration, this ability is mostly lost, and the dimers inhibit the relaxation activity of topoisomerase I. Thus, we suppose that the active, dimeric protoberberines strongly bind to plasmid DNA at elevated drug concentration. This most likely results in blocking the enzyme's access to plasmid DNA, thus inhibiting its relaxation.
Qin
Yong
Y
School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
Pang
Ji-Yan
JY
Chen
Wen-Hua
WH
Zhao
Zhong-Zhen
ZZ
Liu
Liang
L
Jiang
Zhi-Hong
ZH
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology; D001600:Berberine Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology; D053837:DNA Cleavage / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D059004:Topoisomerase I Inhibitors
D000470:Alkaloids; D001600:Berberine Alkaloids; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; C009090:protoberberine; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin