2. Academic Validation
  3. Design, synthesis, and biological evaluation of novel benzo[6,7]indolo[3,4-c]isoquinolines as anticancer agents with topoisomerase I inhibition

Design, synthesis, and biological evaluation of novel benzo[6,7]indolo[3,4-c]isoquinolines as anticancer agents with topoisomerase I inhibition

  • Bioorg Med Chem Lett. 2024 Mar 20:104:129710. doi: 10.1016/j.bmcl.2024.129710.
Kie Sakai 1,  Taisei Soshima 1,  Yuki Hirose 1,  Fumito Ishibashi 2,  Shotaro Hirao 3
Affiliations

Affiliations

  • 1 Faculty of Fisheries, Nagasaki University, Nagasaki, Japan.
  • 2 Faculty of Fisheries, Nagasaki University, Nagasaki, Japan; Graduate School of Fisheries and Environmental Sciences, Nagasaki University, Nagasaki, Japan.
  • 3 Faculty of Science and Technology, Oita University, Dannoharu, Japan. Electronic address: hirao-shoutarou@oita-u.ac.jp.
PMID: 38518997 DOI: 10.1016/j.bmcl.2024.129710
Abstract

A novel series of benzo[6,7]indolo[3,4-c]isoquinolines 3a-3f was designed by scaffold hopping of Topoisomerase I inhibitor benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-ones (BBPIs), which were developed by structural modification of the natural marine product lamellarin. The unconventional pentacycle was constructed by Bischler-Napieralski-type condensation of amide 11 and subsequent intramolecular Heck reaction. In vitro Anticancer activity of the synthesized benzo[6,7]indolo[3,4-c]isoquinolines was evaluated on a panel of 39 human Cancer cell lines (JFCR39). Among the compounds tested, N-(3-morpholinopropyl) derivative 3e showed the most potent antiproliferative activity, with a mean GI50 value of 39 nM. This compound inhibited Topoisomerase I activity by stabilizing the enzyme-DNA complex.

Keywords

Benzo[6,7]indolo[3,4-c]isoquinoline; In vitro anticancer activity; Lamellarin; Scaffold hopping; Topoisomerase I inhibitor.

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