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Synthesis of thiazole linked indolyl-3-glyoxylamide derivatives as tubulin polymerization inhibitors
- Source :
- European journal of medicinal chemistry. 138
- Publication Year :
- 2017
-
Abstract
- A series of thiazole linked indolyl-3-glyoxylamide derivatives were synthesized and evaluated for their in vitro cytotoxic activity against DU145 (prostate), PC-3 (prostate), A549 (lung) and HCT-15 (colon) cancer cell lines by employing the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all the synthesized compounds, compound 13d displayed cytotoxicity of IC50 = 93 nM towards DU145 cancer cell line. The most active compound 13d was also tested on RWPE-1 cells and was found to be safe compared to the DU145 cells. The target compounds were also evaluated for their inhibition activity of tubulin polymerization. Further, the treatment of compound 13d on DU145 cells led to the inhibition of cell migration ability. The detailed studies such as acridine orange/ethidium Bromide (AO/EB), DAPI, annexin V-FITC/propidium iodide staining assay suggested that the compound 13d induced apoptosis in DU145 cells. The influence of the cytotoxic compound 13d on the cell cycle distribution was assessed on the DU145 cell line, exhibiting a cell cycle arrest at the G2/M phase. Moreover, the treatment with compound 13d caused collapse of mitochondrial membrane potential and elevated intracellular ROS levels in DU145 cells. The results from molecular modelling studies revealed that these compounds bind at the colchicine binding site of the tubulin. Thus, this new molecular scaffold could be a new lead for the development of anticancer agents that target tubulin.
- Subjects :
- Antineoplastic Agents
Apoptosis
urologic and male genital diseases
01 natural sciences
Polymerization
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
0302 clinical medicine
DU145
Tubulin
Cell Line, Tumor
Drug Discovery
Humans
Propidium iodide
Cytotoxicity
Thiazole
Cell Proliferation
Pharmacology
Membrane Potential, Mitochondrial
biology
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Cell growth
Organic Chemistry
Acridine orange
General Medicine
Cell Cycle Checkpoints
Molecular biology
Amides
0104 chemical sciences
Thiazoles
Biochemistry
chemistry
Cell culture
030220 oncology & carcinogenesis
biology.protein
Drug Screening Assays, Antitumor
Subjects
Details
- ISSN :
- 17683254
- Volume :
- 138
- Database :
- OpenAIRE
- Journal :
- European journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....59adfb7c9c5a15ce32409df966c30f3d