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

Nagula Shankaraiah; Shalini Nekkanti; Uma Rani BrahmaNiggula Praveen KumarNamrata DeshpandeDaasi PrasannaKishna Ram SenwarUppu Jaya Lakshmi

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

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

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Graphical abstract Display Omitted Highlights ? 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. Abstract 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 IC 50 of 1.48 ± 0.19 μM. The compound 4a showed significant inhibition of tubulin polymerization and disruption of the formation of microtubules (IC 50 of 9.66 ± 0.06 μM). 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. >

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《Bioorganic and medicinal chemistry》 |2017年第17期|4805-4816|共12页
作者
Nagula Shankaraiah; Shalini Nekkanti; Uma Rani BrahmaNiggula Praveen KumarNamrata DeshpandeDaasi PrasannaKishna Ram SenwarUppu Jaya Lakshmi;
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作者单位

Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and;

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research;

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正文语种英语
中图分类药学;
关键词
Heterocycles; Anticancer activity; Chalcones; Aldol condensation; Tubulin polymerization inhibitor; Molecular modeling;

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

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