Synthesis and biological evaluation of 6-substituted indolizinoquinolinediones as catalytic DNA topoisomerase I inhibitors

• DOI: 10.1016/j.ejmech.2015.07.007
• Publication Date: 2015-07-08T01:09:39Z
• Authors: Le-Mao Yu; Xiao-Ru Zhang; Xiao-Bing Li; Yuan Yang; Hong-Yu Wei; Xi-Xin He; Lian-Quan Gu; Zhi-Shu Huang; Yves Pommier; Lin-Kun An
• Keywords: 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; Indolizines; Antineoplastic Agents; Quinolones; 3. Good health; Structure-Activity Relationship; 03 medical and health sciences; DNA Topoisomerases, Type I; Biocatalysis; Tumor Cells, Cultured; Humans; Drug Screening Assays, Antitumor; Topoisomerase I Inhibitors; Cell Proliferation

In our previous work, indolizinoquinolinedione derivative 1 was identified as a Top1 catalytic inhibitor. Herein, a series of 6-substituted indolizinoquinolinedione derivatives were synthesized through modification of the parent compound 1. Top1 cleavage and relaxation assays indicate that none of these novel compounds act as classical Top1 poison, and that the compounds with alkylamino terminus at C-6 side chain, including 8, 11-16, 18-21, 25, 26 and 28-30, are the most potent Top1 catalytic inhibitors. Top1-mediated unwinding assay demonstrated that 14, 22 and 26 were Top1 catalytic inhibitors without Top1-mediated unwinding effect. Moreover, MTT results showed that compounds 26, 28-30 exhibit significant cytotoxicity against human leukemia HL-60 cells, and that compound 26 exerts potent cytotoxicity against A549 lung cancer cells at nanomolar range.