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Spirooxindole-derived morpholine-fused-1,2,3-triazoles: Design, synthesis, cytotoxicity and apoptosis inducing studies
- Source :
- European Journal of Medicinal Chemistry. 102:413-424
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- A series of new spirooxindole-derived morpholine-fused-1,2,3-triazole derivatives has been synthesized from isatin spiro-epoxides. The protocol involves regiospecific isatin-epoxide ring opening with azide nucleophile followed by sequential O-propargylation, and intramolecular 1,3-dipolar cycloaddition reaction. These compounds have been evaluated for their antiproliferative activity against selected human tumor cell lines of lung (A549), breast (MCF-7), cervical (HeLa), and prostate (DU-145). Among the tested compounds, 6i, 6n and 6p showed potent growth inhibition against A549 cell line with IC50 values in the range of 1.87-4.36 μM, which are comparable to reference standards doxorubicin and 5-flourouracil. The compounds 6i and 6p treated A549 cells displayed typical apoptotic morphological features such as cell shrinkage, nuclear condensation, fragmentation, and decreased migration potential. Flow-cytometry analysis revealed that the compounds arrested the cells in G2/M phase of cell cycle. Hoechst and acridine orange/ethidium bromide staining studies also showed that the cell proliferation was inhibited through induction of apoptosis. Moreover, the compounds treatment led to collapse of the mitochondrial membrane potential (DΨm) and increased levels of reactive oxygen species (ROS) were noted in A549 cells.
- Subjects :
- Indoles
Morpholines
Antineoplastic Agents
Apoptosis
HeLa
Structure-Activity Relationship
chemistry.chemical_compound
Cell Line, Tumor
Drug Discovery
Humans
Spiro Compounds
Fragmentation (cell biology)
Cell Proliferation
Pharmacology
A549 cell
Dose-Response Relationship, Drug
Molecular Structure
biology
Cytotoxins
Cell growth
Chemistry
Cell Cycle
Organic Chemistry
Acridine orange
General Medicine
Triazoles
Cell cycle
biology.organism_classification
Biochemistry
Cell culture
Drug Design
Drug Screening Assays, Antitumor
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 102
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....5911b210d8765d01bd62dfc301eaa851