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Novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives as topoisomerase I inhibitors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2017 Feb 15; Vol. 127, pp. 187-199. Date of Electronic Publication: 2016 Dec 20. - Publication Year :
- 2017
-
Abstract
- In this study, two series of novel 4-(4-substituted amidobenzyl)furan-2(5H)-one derivatives containing an α,β-unsaturated lactone fragment were synthesized and screened for Topo I inhibition and antitumor activity. The topoisomerase I inhibitory activities and cytotoxicities against three human cancer cell lines (MCF-7,Hela,A549) were evaluated. The results revealed that series 2, compounds bearing an exocyclic double bond on the furanone ring, generally showed more potent activity than series 1, compounds lacking an exocyclic double bond. Several compounds of series 2 possess significant Topo I inhibitory activity and potent antiproliferative activity against cancer cell lines. Further mechanism studies of the most active compound of series 2 (B-15) indicated that synthetic compounds can not only stabilize the drug-enzyme-DNA covalent ternary complex as well as camptothecin, but also interfere with the binding between Topo I and DNA. The binding patterns of these compounds with Topo I and structure-activity relationships are discussed.<br /> (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Antineoplastic Agents metabolism
Cell Line, Tumor
Cell Proliferation drug effects
DNA Cleavage drug effects
DNA Topoisomerases, Type I chemistry
Dose-Response Relationship, Drug
Drug Design
Furans metabolism
Humans
Molecular Docking Simulation
Nucleic Acid Conformation
Protein Conformation
Structure-Activity Relationship
Topoisomerase I Inhibitors metabolism
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
DNA Topoisomerases, Type I metabolism
Furans chemistry
Furans pharmacology
Topoisomerase I Inhibitors chemistry
Topoisomerase I Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 127
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 28063351
- Full Text :
- https://doi.org/10.1016/j.ejmech.2016.12.035