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Discovery, synthesis and biological evaluation of cycloprotoberberine derivatives as potential antitumor agents.
来源: 时间:2014-07-08 浏览次数:3142
Eur J Med Chem. 2013 Oct;68:463-72. doi: 10.1016/j.ejmech.2013.07.026. Epub 2013 Aug 11.
Discovery, synthesis and biologicalevaluation of cycloprotoberberine derivatives as potential antitumor agents.
  • Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
Abstract
A series of new 1,13-cycloprotoberberine derivatives defined through variations at the 9-position were designed, synthesized and evaluated for their cytotoxicities in human HepG2 (hepatoma), HT1080 (fibrosarcoma) and HCT116 (colon cancer) cells. The preliminary structure-activity relationship (SAR) revealed that the replacement of 9-methoxyl with an ester moiety might significantly enhance the antiproliferative activity in vitro. Notably, compound 7f demonstrated equipotent cytotoxicity activity against breast cancer MCF-7 (parent) and doxorubicin (DOX)-resistant MCF-7 (MCF-7/ADrR) cells, indicating a mode of action different from that of DOX. Further mechanism study showed that 7f significantly inhibited activity of DNA topoisomerase I (Top I) and Top II. G2/M phase arrest and tumor cell growth reduction was observed thereafter. Thus, we consider cycloprotoberberine analogues to be a new family of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells.
Copyright © 2013 Elsevier Masson SAS. All rights reserved.
KEYWORDS:
Antiproliferative, Cycloprotoberberine, Drug resistance, Structure−activity relationship, Topoisomerase