Document Detail

New C5-alkylated indolobenzazepinones acting as inhibitors of tubulin polymerization: cytotoxic and antitumor activities.
MedLine Citation:
PMID:  18503262     Owner:  NLM     Status:  MEDLINE    
A series of 5-alkylindolobenzazepin-7-ones was synthesized by Suzuki coupling between 3-iodoindole-2-carboxylates and the appropriate alpha-alkylbenzylamino o-boronic acids followed by cyclization to the lactam. Derivatives having a linear alkyl chain at C5 were found to be highly cytotoxic to KB cells with IC50 values in the 30-80 nM range. These compounds also inhibited the polymerization of tubulin with IC50's of 1-2 microM. Compound 4f (( S)-5-ethyl) showed comparable antiproliferative activities (IC50's of 30-70 nM) in a variety of cancer cell lines, cell growth being arrested at the G2/M phase. Compound 4f induced apoptosis in a dose-dependent manner in three different cancer cell lines and was shown to affect cell morphology in a manner consistent with its inhibitory action on tubulin polymerization. Using the experimental model of glioma grafted on the chick chorio-allantoic membrane, local treatment with compound 4f markedly reduced tumor progression.
Laurent Keller; Stéphane Beaumont; Jian-Miao Liu; Sylviane Thoret; Jérôme S Bignon; Joanna Wdzieczak-Bakala; Philippe Dauban; Robert H Dodd
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-05-27
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  51     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2008 Jun 
Date Detail:
Created Date:  2008-06-19     Completed Date:  2008-09-05     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3414-21     Citation Subset:  IM    
Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
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MeSH Terms
Apoptosis / drug effects
Benzazepines / chemical synthesis*,  chemistry,  pharmacology
Cell Cycle / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Chick Embryo
Drug Screening Assays, Antitumor
Indoles / chemical synthesis*,  chemistry,  pharmacology
Neoplasm Transplantation
Structure-Activity Relationship
Transplantation, Heterologous
Tubulin / chemistry
Tubulin Modulators / chemical synthesis*,  chemistry,  pharmacology
Reg. No./Substance:
0/5-ethyl-5,8-dihydroindolo(2,3-d)(2)benzazepin-7(6H)-one; 0/Benzazepines; 0/Biopolymers; 0/Indoles; 0/Tubulin; 0/Tubulin Modulators

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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