合成不同杂环连接的查尔酮共轭物作为细胞毒性剂和微管蛋白聚合抑制剂。

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

作者信息

Shankaraiah Nagula, Nekkanti Shalini, Brahma Uma Rani, Praveen Kumar Niggula, Deshpande Namrata, Prasanna Daasi, Senwar Kishna Ram, Jaya Lakshmi Uppu

机构信息

Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India.

出版信息

Bioorg Med Chem. 2017 Sep 1;25(17):4805-4816. doi: 10.1016/j.bmc.2017.07.031. Epub 2017 Jul 21.

DOI:10.1016/j.bmc.2017.07.031

PMID:28774575

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 of 1.48±0.19µM. The compound 4a showed significant inhibition of tubulin polymerization and disruption of the formation of microtubules (IC 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.

摘要

通过改变不同的烷烃间隔基，设计并合成了一系列新的杂环连接查尔酮共轭物。通过MTT法测试了这些共轭物对一组选定的人类癌细胞系的体外细胞毒性潜力，这些细胞系包括肺癌（A549和NCI-H460）、前列腺癌（DU-145和PC-3）、结肠癌（HCT-15和HCT-116）和脑癌（U-87胶质母细胞瘤）。值得注意的是，在所有测试化合物中，4a对NCI-H460（肺癌）细胞表现出强大的细胞毒性，IC50为1.48±0.19µM。化合物4a对微管蛋白聚合有显著抑制作用，并破坏微管的形成（IC50为9.66±0.06μM）。此外，相差显微镜和DAPI染色研究表明，化合物4a可诱导NCI-H460细胞凋亡。进一步的流式细胞术分析显示，化合物4a使NCI-H460细胞停滞在细胞周期的G2/M期。此外，将最具活性的化合物4a和4b与微管蛋白的秋水仙碱位点进行分子对接研究，揭示了这些新共轭物可能的相互作用模式。