期刊
CHEMMEDCHEM
卷 14, 期 24, 页码 2052-2060出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201900541
关键词
combretastatin A4; sulfonyl piperazine; tubulin assembly; cell migration; scratch wound assay; cytotoxicity
资金
- DoP, Ministry of Chemicals & Fertilizers, Govt. of India, New Delhi
- SERB, DST, Govt. of India [YSS-2015-001709]
Molecular hybridization approach is a promising structural modification tool to design new chemical entities (NCEs) by mimicking two different pharmacophoric units into one scaffold to enhance the biological properties. With this aim, combretastatin-A4 acids were integrated with sulfonyl piperazine scaffolds as a one molecular platform and evaluated for their in vitro antiproliferative activity against a panel of human cancer lines cell lines namely, lung (A549), mouse melanoma (B16F10), breast (MDA MB-231and MCF-7) and colon (HCT-15) by MTT assay. Amongst which the compound (E)-3-(4-Chlorophenyl)-1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (5 ab) displayed significant IC50 values in the range of 0.36 to 7.08 mu m against the selected cancer cell lines. Moreover, 5 ab was found to be the most potent member of this series with IC50 0.36 +/- 0.02 mu m. Further investigations revealed that the compound 5 ab displayed significant inhibition of tubulin assembly with IC50 5.24 +/- 0.06 mu m and molecular docking studies also disclosed the binding of 5 ab effectively in CA4 binding space at the colchicine binding site. The flow cytometric analysis demonstrated that the compound 5 ab caused cell cycle arrest at G2/M phase in A549 cells. Compound 5 ab induced apoptosis in A549 cells which was further evaluated by different staining assays such as DAPI and AO which undoubtedly speculated, the induction of apoptosis. To study the anti-migration with 5 ab, cell migration/scratch wound assay was performed and the extent of apoptosis was studied by Annexin-V, including mitochondrial potential by JC-1 staining.
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