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Synthesis, anticancer effect and molecular modeling of new thiazolylpyrazolyl coumarin derivatives targeting VEGFR-2 kinase and inducing cell cycle arrest and apoptosis.

Abstract：

:New thiazolylpyrazolyl coumarin derivatives were synthesized and tested for their anticancer potential in vitro against five different human cell lines, including breast MCF-7, lung A549, prostate PC3, liver HepG2 and normal melanocyte HFB4. Breast carcinoma revealed higher sensitivity towards compounds 7a, 8c, 9b, 9c and 9d with IC50 values ranging from 5.41 to 10.75 μM in comparison to the reference drug doxorubicin (IC50 = 6.73 μM). In addition, no noticeable toxicity was exhibited towards normal cells HFB4. Moreover, in vitro studies of the VEGFR-2 inhibition in human breast cancer MCF-7 cell line for the promising cytotoxic compounds showed that compounds 7a, 8c, 9b, 9c and 9d were potent inhibitors at low micromolar concentrations (IC50 = 0.034-0.582 μM) compared to the reference drug, sorafenib (IC50 = 0.019 μM). Several theoretical and experimental studies were done to reveal the molecular mechanisms that control breast carcinoma metastasis. The mechanistic effectiveness in cell cycle progression, apoptotic induction and gene regulation were assessed for the promising compound 9d due to its remarkable cytotoxic activity against MCF-7 and significant VEGFR-2 inhibition. Flow cytometeric analysis showed that compound 9d induced cell growth cessation at G2/M phase and increased the percentage of cells at pre-G1 phase that stimulates the apoptotic death of MCF-7 cells. Furthermore, real time PCR assay illustrated that compound 9d up regulated p53 gene expression and elevated Bax/Bcl-2 ratio which confirmed the mechanistic pathway of compound 9d. Moreover, the apoptotic induction of breast cancer cells MCF-7 was enhanced effectively through activation of caspases-7 and 9 by compound 9d. On the other hand, a set of in silico methods such as molecular docking, molecular dynamics simulation, QSAR analysis as well as ADMET analysis was performed in order to study the protein-ligand interactions and the relationship between the physicochemical properties and the inhibitory activity of the promising compounds 7a, 8c and 9d. Based on the aforementioned findings, compound 9d could be considered as effective apoptosis modulator and promising lead for future development of new anti-breast cancer agents.

journal_name

Bioorg Chem

journal_title

Bioorganic chemistry

authors

Mohamed TK,Batran RZ,Elseginy SA,Ali MM,Mahmoud AE

doi

10.1016/j.bioorg.2018.12.040

subject

Has Abstract

pub_date

2019-04-01 00:00:00

pages

253-273

eissn

0045-2068

issn

1090-2120

pii

S0045-2068(18)31201-X

journal_volume

pub_type

杂志文章

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Synthesis, anticancer effect and molecular modeling of new thiazolylpyrazolyl coumarin derivatives targeting VEGFR-2 kinase and inducing cell cycle arrest and apoptosis.