Synthesis of substituted biphenyl methylene indolinones as apoptosis inducers and tubulin polymerization inhibitors

Donthiboina, Kavitha; Anchi, Pratibha; Ramya, P.V. Sri; Karri, Shailaja; Srinivasulu, Gannoju; Godugu, Chandraiah; Shankaraiah, Nagula; Kamal, Ähmed

doi:10.1016/j.bioorg.2019.01.063

Cited by 28 publications

(9 citation statements)

References 24 publications

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“…ROS accumulations were also frequently observed after the treatment of CBSIs. [ 26 ] Therefore, we evaluated ROS production in HCC cells using the fluorescent probe DCFH‐DA by flow cytometry and fluorescence microscopy. The intracellular ROS accumulations were markedly increased after W463 treatment in HCC cells (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

W436, a novel SMART derivative, exhibits anti‐hepatocarcinoma activity by inducing apoptosis and G2/M cell cycle arrest in vitro and in vivo and induces protective autophagy

Man

Sun

et al. 2021

J Biochem & Molecular Tox

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Hepatocellular carcinoma (HCC) is considered one of the most common primary liver cancers and the second leading cause of cancer‐associated mortality around the world annually. Therefore, it is urgent to develop novel drugs for HCC therapy. We synthesized a novel 4‐substituted‐methoxybenzoyl‐aryl‐thiazole (SMART) analog, (5‐(4‐aminopiperidin‐1‐yl)‐2‐phenyl‐2H‐1,2,3‐triazol‐4‐yl) (3,4,5‐trimethoxyphenyl) methanone (W436), with higher solubility, stability, and antitumor activity than SMART against HCC cells in vivo. The purpose of this study was to investigate the mechanisms by which W436 inhibited cell growth in HCC cells. We observed that W436 inhibited the proliferation of HepG2 and Hep3B cells in a dose‐dependent manner. Importantly, the anticancer activity of W436 against HCC cells was even higher than that of SMART in vivo. In addition, the antiproliferative effects of W436 on HCC cells were associated with G2/M cell cycle arrest and apoptosis via the activation of reactive oxygen species‐mediated mitochondrial apoptotic pathway. W436 also induced protective autophagy by inhibiting the protein kinase B/mammalian target of rapamycin pathway. At the same time, W436 treatment inhibited the cell adhesion and invasion as well as the process of epithelial‐to‐mesenchymal transition Taken together, our results showed that W436 had the promising potential for the therapeutic treatment of HCC with improved solubility, stability, and bioavailability.

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Section: Resultsmentioning

confidence: 99%

W436, a novel SMART derivative, exhibits anti‐hepatocarcinoma activity by inducing apoptosis and G2/M cell cycle arrest in vitro and in vivo and induces protective autophagy

Man

Sun

et al. 2021

J Biochem & Molecular Tox

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“…We also investigated the effects of compounds in inducing A549 cells apoptosis using fluorescence microscope by staining with DAPI [ 34 , 35 ]. The results in Figure 7 A indicate that the nuclear structure of the control cells was intact with round shape while the A549 cells treated with the 4d and 4n showed nuclear concentration and micronuclei formation.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Anti-Tumor Activity of Novel Benzimidazole-Chalcone Hybrids as Non-Intercalative Topoisomerase II Catalytic Inhibitors

et al. 2020

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Chemical diversification of type II topoisomerase (Topo II) inhibitors remains indispensable to extend their anti-tumor therapeutic values which are limited by their side effects. Herein, we designed and synthesized a novel series of benzimidazole-chalcone hybrids (BCHs). These BCHs showed good inhibitory effect in the Topo II mediated DNA relaxation assay and anti-proliferative effect in 4 tumor cell lines. 4d and 4n were the most potent, with IC50 values less than 5 μM, superior to etoposide. Mechanistic studies indicated that the BCHs functioned as non-intercalative Topo II catalytic inhibitors. Moreover, 4d and 4n demonstrated versatile properties against tumors, including inhibition on the colony formation and cell migration, and promotion of apoptosis of A549 cells. The structure-activity relationship and molecular docking analysis suggested possible contribution of the chalcone motif to the Topo II inhibitory and anti-proliferative potency. These results indicated that 4d and 4n could be promising lead compounds for further anti-tumor drug research.

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“…According to literature, monohalogenated derivatives are broadly applied in biological studies and present better results due to lower persistence and better absorption and distribution in vivo. [8][9][10]23] In view of the results outlined above, three promising derivatives (4, 5 and 17) were selected, on the basis of their high activity levels, to perform a cell viability study at various concentrations (from 0.1 to 100 μM) in tumoral (HeLa) and nontumoral (HEK-293, human embryonic kidney) cell lines for 24 h to study their selectivity. The data were compared to those of the clinically used anticancer drug etoposide (Figure 5).…”

Section: Bioactivity Studiesmentioning

confidence: 99%

Acyl Derivatives of Eudesmanolides To Boost their Bioactivity: An Explanation of Behavior in the Cell Membrane Using a Molecular Dynamics Approach

et al. 2021

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Semisynthetic analogs of natural products provide an important approach to obtain safer and more active drugs and they can also have enhanced physicochemical properties such as persistence, cross-membrane processes and bioactivity. Acyl derivatives of different natural product families, from sesquiterpene lactones to benzoxazinoids, have been synthesized and tested in our laboratories. These compounds were evaluated against tumoral and nontumoral cell lines to identify selective derivatives with a reduced negative impact upon application.The mode of action of these compounds was analyzed by anticaspase-3 assays and molecular dynamics simulations with cell membrane re-creation were also carried out. Aryl derivatives of eudesmanolide stand out from the other compounds and are better than current anticancer drugs such as etoposide in terms of selectivity and activity. Computational studies provide evidence that lipophilicity plays a key role and the 4fluorobenzoyl derivative can pass easily through the cell membrane.

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Synthesis of substituted biphenyl methylene indolinones as apoptosis inducers and tubulin polymerization inhibitors

Cited by 28 publications

References 24 publications

W436, a novel SMART derivative, exhibits anti‐hepatocarcinoma activity by inducing apoptosis and G2/M cell cycle arrest in vitro and in vivo and induces protective autophagy

W436, a novel SMART derivative, exhibits anti‐hepatocarcinoma activity by inducing apoptosis and G2/M cell cycle arrest in vitro and in vivo and induces protective autophagy

Design, Synthesis and Anti-Tumor Activity of Novel Benzimidazole-Chalcone Hybrids as Non-Intercalative Topoisomerase II Catalytic Inhibitors

Acyl Derivatives of Eudesmanolides To Boost their Bioactivity: An Explanation of Behavior in the Cell Membrane Using a Molecular Dynamics Approach

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