Synthesis of different heterocycles-linked chalcone conjugates as cytotoxic agents and tubulin polymerization inhibitors

• Published in: Bioorganic & medicinal chemistry 2017-09, Vol.25 (17), p.4805-4816
• Main Authors: Shankaraiah, Nagula, Nekkanti, Shalini, Brahma, Uma Rani, Praveen Kumar, Niggula, Deshpande, Namrata, Prasanna, Daasi, Senwar, Kishna Ram, Jaya Lakshmi, Uppu
• Format: Article
• Language: English
• Subjects: A549 Cells; Aldol condensation; Anticancer activity; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Binding Sites; Cell Line, Tumor; Chalcone - chemical synthesis; Chalcone - chemistry; Chalcone - pharmacology; Chalcone - toxicity; Chalcones; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints - drug effects; HCT116 Cells; Heterocycles; Humans; Inhibitory Concentration 50; M Phase Cell Cycle Checkpoints - drug effects; Membrane Potential, Mitochondrial; Microscopy, Phase-Contrast; Molecular Docking Simulation; Molecular modeling; Protein Structure, Tertiary; Structure-Activity Relationship; Tubulin - chemistry; Tubulin - metabolism; Tubulin Modulators - chemical synthesis; Tubulin Modulators - pharmacology; Tubulin Modulators - toxicity; Tubulin polymerization inhibitor
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.07.031

[Display omitted] •New heterocycles-linked chalcone conjugates were synthesized.•Anticancer activity was tested on selected human cancer cell lines.•The compound 4a effectively inhibited polymerization of tubulin in a cell-free assay.•4a induced apoptosis and generation of ROS on NCI-H460 cells.•4a arrested on NCI-H460 cells in G2/M phase of cell cycle. A series of new heterocycles-linked chalcone conjugates has been designed and synthesized by varying different alkane spacers. These conjugates were tested for their in vitro cytotoxic potential against a panel of selected human cancer cell lines namely, lung (A549 and NCI-H460), prostate (DU-145 and PC-3), colon (HCT-15 and HCT-116), and brain (U-87 glioblastoma) by MTT assay. Notably, among all the tested compounds, 4a exhibited potent cytotoxicity on NCI-H460 (lung cancer) cells with IC50 of 1.48±0.19µM. The compound 4a showed significant inhibition of tubulin polymerization and disruption of the formation of microtubules (IC50 of 9.66±0.06μM). Moreover, phase contrast microscopy and DAPI staining studies indicated that compound 4a can induce apoptosis in NCI-H460 cells. Further, the flow-cytometry analysis revealed that compound 4a arrests NCI-H460 cells in the G2/M phase of the cell cycle. In addition, molecular docking studies of the most active compounds 4a and 4b into the colchicine site of the tubulin, revealed the possible mode of interaction by these new conjugates.