title: Inhibition of DNA topoisomerase I by natural and synthetic mono- and dimeric protoberberine alkaloids.
abstract: 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.
authors: School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors: Yong
authors: Y
authors: Qin
authors: Ji-Yan
authors: JY
authors: Pang
authors: Wen-Hua
authors: WH
authors: Chen
authors: Zhong-Zhen
authors: ZZ
authors: Zhao
authors: Liang
authors: L
authors: Liu
authors: Zhi-Hong
authors: ZH
authors: Jiang
mesh_terms: 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
chemical_list: D000470:Alkaloids; D001600:Berberine Alkaloids; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; C009090:protoberberine; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin