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Modified carbazoles destabilize microtubules and kill glioblastoma multiform cells
- Source :
- European journal of medicinal chemistry. 159
- Publication Year :
- 2018
-
Abstract
- Small molecules that target microtubules (MTs) represent promising therapeutics to treat certain types of cancer, including glioblastoma multiform (GBM). We synthesized modified carbazoles and evaluated their antitumor activity in GBM cells in culture. Modified carbazoles with an ethyl moiety linked to the nitrogen of the carbazole and a carbonyl moiety linked to distinct biaromatic rings exhibited remarkably different killing activities in human GBM cell lines and patient-derived GBM cells, with IC50 values from 67 to >10,000 nM. Measures of the activity of modified carbazoles with tubulin and microtubules coupled to molecular docking studies show that these compounds bind to the colchicine site of tubulin in a unique low interaction space that inhibits tubulin assembly. The modified carbazoles reported here represent novel chemical tools to better understand how small molecules disrupt MT functions and kill devastating cancers such as GBM.
- Subjects :
- 0301 basic medicine
Cell Survival
Carbazoles
Antineoplastic Agents
Microtubules
Article
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
Microtubule
Cell Line, Tumor
Drug Discovery
Colchicine
Moiety
Structure–activity relationship
Humans
Cell Proliferation
Pharmacology
biology
Dose-Response Relationship, Drug
Molecular Structure
Chemistry
Cell growth
Organic Chemistry
General Medicine
Small molecule
Molecular Docking Simulation
030104 developmental biology
Tubulin
Cell culture
biology.protein
Biophysics
Drug Screening Assays, Antitumor
Glioblastoma
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 159
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....a257fe135e297aa37be8e4ba2701ea75