Lamellarin-inspired potent topoisomerase I inhibitors with the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one scaffold

• Fukuda, Tsutomu

• Nanjo, Yusuke

• Fujimoto, Masahiro

• Yoshida, Kenyu

• Natsui, Yuko

• Ishibashi, Fumito

• Okazaki, Fumiyasu

• To, Hideto

• Iwao, Masatomo

Abstract

A new class of topoisomerase I inhibitors containing the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one (abbreviated as BBPI) ring system have been developed based on structure-activity relationship studies of the cytotoxic marine alkaloid lamellarin D. The pentacyclic BBPI scaffold was constructed from N-tert-butoxycarbonylpyrrole by sequential and regioselective functionalization of the pyrrole core using directed lithiation, conventional electrophilic substitution, and palladium-catalyzed cross-coupling reactions. Further N-alkylation of the scaffold followed by selective deprotection of the O-isopropyl group produced a range of N-substituted BBPI derivatives. The BBPIs thus prepared exhibited potent topoisomerase I inhibitory activity in DNA relaxation assays. The activities of BBPIs were higher than those of lamellarin D and camptothecin; they showed potent and selective antiproliferative activity in the panel of 39 human cancer cell lines established by Japanese Foundation for Cancer Research. COMPARE analyses indicated that the inhibition patterns of the BBPIs correlated well with those of the known topoisomerase I inhibitors such as SN-38 and TAS-103. The water-soluble valine ester derivative exhibited antitumor activity in vivo against murine colon carcinoma colon 26. The activity was comparable to that of the approved anticancer agent irinotecan.

Bioorganic & Medicinal Chemistry, 27(2), pp.265-277; 2019

Journal

• Bioorganic & Medicinal Chemistry

  Bioorganic & Medicinal Chemistry 27 (2), 265-277, 2019-01-15

  Elsevier Ltd.

Keywords

• Topoisomerase I inhibitors
• Lamellarin D
• BBPI
• Scaffold hopping
• Antitumor activity

Details

• CRID: 1050287297275585792
• NII Article ID: 120006987774
• ISSN: 09680896
• DOI: 10.1016/j.bmc.2018.11.037
• HANDLE: 10069/38935
• Web Site: https://nagasaki-u.repo.nii.ac.jp/records/1662
• Web Site: https://api.elsevier.com/content/article/PII:S0968089618315232?httpAccept=text/xml
• Web Site: https://api.elsevier.com/content/article/PII:S0968089618315232?httpAccept=text/plain
• Text Lang: en
• Article Type: journal article
• Data Source:
  • IRDB
  • Crossref
  • CiNii Articles
  • KAKEN