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Design, synthesis, and biological evaluation of novel benzo[6,7]indolo[3,4-c]isoquinolines as anticancer agents with topoisomerase I inhibition.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2024 May 15; Vol. 104, pp. 129710. Date of Electronic Publication: 2024 Mar 20. - Publication Year :
- 2024
-
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 GI <subscript>50</subscript> value of 39 nM. This compound inhibited topoisomerase I activity by stabilizing the enzyme-DNA complex.<br />Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Subjects :
- Humans
Cell Line, Tumor
Cell Proliferation drug effects
DNA Topoisomerases, Type I metabolism
Drug Screening Assays, Antitumor
Structure-Activity Relationship
Drug Design
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Isoquinolines chemical synthesis
Isoquinolines chemistry
Isoquinolines pharmacology
Topoisomerase I Inhibitors chemical synthesis
Topoisomerase I Inhibitors chemistry
Topoisomerase I Inhibitors pharmacology
Coumarins chemical synthesis
Coumarins chemistry
Coumarins pharmacology
Heterocyclic Compounds, 4 or More Rings chemical synthesis
Heterocyclic Compounds, 4 or More Rings chemistry
Heterocyclic Compounds, 4 or More Rings pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 104
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 38518997
- Full Text :
- https://doi.org/10.1016/j.bmcl.2024.129710