DSpace university logo mark
Advanced Search
Japanese | English 

NAOSITE : Nagasaki University's Academic Output SITE > Faculty of Engineering > Articles in academic journal >

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


File Description SizeFormat
BMC27_265.pdf1.51 MBAdobe PDFEmbargo until 2021-01-15
Supplementary_data.pdf6.05 MBAdobe PDFEmbargo until 2021-01-15

Title: Lamellarin-inspired potent topoisomerase I inhibitors with the unprecedented benzo[g][1]benzopyrano[4,3-b]indol-6(13H)-one scaffold
Authors: Fukuda, Tsutomu / Nanjo, Yusuke / Fujimoto, Masahiro / Yoshida, Kenyu / Natsui, Yuko / Ishibashi, Fumito / Okazaki, Fumiyasu / To, Hideto / Iwao, Masatomo
Issue Date: 15-Jan-2019
Publisher: Elsevier Ltd.
Citation: Bioorganic & Medicinal Chemistry, 27(2), pp.265-277; 2019
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.
Keywords: Topoisomerase I inhibitors / Lamellarin D / BBPI / Scaffold hopping / Antitumor activity
URI: http://hdl.handle.net/10069/38935
ISSN: 09680896
DOI: 10.1016/j.bmc.2018.11.037
Rights: ©2018, Elsevier. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/
Type: Journal Article
Text Version: author
Appears in Collections:Articles in academic journal

Citable URI : http://hdl.handle.net/10069/38935

All items in NAOSITE are protected by copyright, with all rights reserved.

 

Valid XHTML 1.0! Copyright © 2006-2015 Nagasaki University Library - Feedback Powerd by DSpace