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Inhibition of DNA Topoisomerase I by Natural and Synthetic Mono‐ and Dimeric Protoberberine Alkaloids
Author(s) -
Qin Yong,
Pang JiYan,
Chen WenHua,
Zhao ZhongZhen,
Liu Liang,
Jiang ZhiHong
Publication year - 2007
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200790040
Subject(s) - topoisomerase , chemistry , camptothecin , dna , stereochemistry , enzyme , cleavage (geology) , alkaloid , biochemistry , biology , paleontology , fracture (geology)
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.