Design, synthesis and biological evaluation of 3-substituted indenoisoquinoline derivatives as topoisomerase I inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2016-02, Vol.26 (3), p.1068-1072
• Main Authors: Zhao, Qian, Xu, Xi, Xie, Zhouling, Liu, Xiao, You, Qidong, Guo, Qinglong, Zhong, Yi, Li, Zhiyu
• Format: Article
• Language: English
• Subjects: Anti-proliferative activity; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; DNA Topoisomerases, Type I - chemistry; DNA Topoisomerases, Type I - metabolism; Drug Design; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Indenoisoquinoline derivatives; Isoquinolines - chemistry; Isoquinolines - pharmacology; Structure-Activity Relationship; Synthesis; Top I inhibitors; Topoisomerase I Inhibitors - chemical synthesis; Topoisomerase I Inhibitors - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2015.12.014

[Display omitted] A new series of indenoisoquinoline derivatives was designed and synthesized. The in vitro anti-proliferative activity of these novel compounds was evaluated in HepG2, A549 and HCT-116 cell lines. Compounds 9a, 9b, 10a, 10c, 10e, 18a and 18b manifested potent inhibitory activity against the three tested cancer cell lines. Nineteen compounds were also tested for Top I inhibition at 50μM. Almost all the tested compounds showed potent Top I inhibition activity at this concentration. The most potent compounds 9a and 10a demonstrated more cytotoxicity than HCPT and TPT and was comparable to CPT in inhibitory activities on Top I in our biological assay.