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

  • Bioorg Med Chem Lett. 2016 Feb 1;26(3):1068-1072. doi: 10.1016/j.bmcl.2015.12.014.
Qian Zhao  1 ,  Xi Xu  1 ,  Zhouling Xie  1 ,  Xiao Liu  1 ,  Qidong You  1 ,  Qinglong Guo  2 ,  Yi Zhong  3 ,  Zhiyu Li  4
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
  • 2. Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
  • 3. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address: [email protected].
  • 4. Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China. Electronic address: [email protected].
PMID: 26725027 DOI: 10.1016/j.bmcl.2015.12.014
Abstract

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 50 μM. 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.

Keywords
Anti-proliferative activity; Indenoisoquinoline derivatives; Synthesis; Top I inhibitors.