Discovery, synthesis and biological evaluation of cycloprotoberberine derivatives as potential antitumor agents

• Published in: European journal of medicinal chemistry 2013-10, Vol.68, p.463-472
• Main Authors: Li, Yang-Biao, Zhao, Wu-Li, Wang, Yan-Xiang, Zhang, Cai-Xia, Jiang, Jian-Dong, Bi, Chong-Wen, Tang, Sheng, Chen, Ru-Xian, Shao, Rong-Guang, Song, Dan-Qing
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antiproliferative; Berberine Alkaloids - chemical synthesis; Berberine Alkaloids - chemistry; Berberine Alkaloids - pharmacology; Binding Sites; Cell Line, Tumor; Cell Survival - drug effects; Crystallography, X-Ray; Cyclization; Cycloprotoberberine; Drug Discovery; Drug resistance; Drug Resistance, Neoplasm - drug effects; Humans; Inhibitory Concentration 50; MCF-7 Cells; Models, Biological; Molecular Docking Simulation; Molecular Structure; Structure−activity relationship; Topoisomerase
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2013.07.026

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. [Display omitted] •Twenty-one cycloprotoberberines were designed and synthesized.•Most of them inhibited cell proliferation against 3 cancer cell lines.•Compound 7f afforded a potent antitumor activity against drug-resistant cells.•Compound 7f had a potential inhibitory activity on both DNA Top I and Top II.