Design, synthesis, antitumor activities and biological studies of novel diaryl substituted fused heterocycles as dual ligands targeting tubulin and katanin

Gao, Feng; Liang, Yuru; Zhou, Pengfei; Cheng, Jing; Ding, Kuiling; Wang, Yang

doi:10.1016/j.ejmech.2019.05.072

Cited by 26 publications

(14 citation statements)

References 35 publications

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“…Numerous studies demonstrate that tubulin polymerization inhibitors are capable of inducing cellular apoptosis [35,36]. To evaluate the mode of cell death induced by 19h, Annexin-V/PI assay was used.…”

Section: Apoptosis Quantification In Mcf-7 Cellsmentioning

confidence: 99%

Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity

et al. 2020

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A novel series of quinoline derivatives of combretastatin A-4 incorporating rigid hydrazone and a cyclic oxadiazole linkers were synthesized and have demonstrated potent tubulin polymerization inhibitory properties. Many of these novel derivatives have shown significant antiproliferative activities in the submicromolar range. The most potent compound, 19h, demonstrated superior IC50 values ranging from 0.02 to 0.04 µM against four cancer cell lines while maintaining low cytotoxicity in MCF-10A non-cancer cells, thereby suggesting 19h’s selectivity towards proliferating cancer cells. In addition to tubulin polymerization inhibition, 19h caused cell cycle arrest in MCF-7 cells at the G2/M phase and induced apoptosis. Collectively, these findings indicate that 19h holds potential for further investigation as a potent chemotherapeutic agent targeting tubulin.

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Section: Apoptosis Quantification In Mcf-7 Cellsmentioning

confidence: 99%

Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity

et al. 2020

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“…As shown in Figure 3 , after tubulin was incubated with 7m at 5, 10, 20 µM, the increased tendency of the fluorescence intensity was obviously slowed down with increasing concentration, with a similar action to that of colchicine. In addition, 7m produces an obvious concentration-dependent inhibition of tubulin polymerization with an IC 50 value of 12.23 µM, which was twofold less potent than that of colchicine (IC 50 = 6.036 µM) ( Gao et al, 2019 ). The results suggested that the mechanism of compound 7m was consistent with previously reported microtubule-destabilizing agents, certifying that compound 7m can act as potential microtubule-destabilizing agents for cancer therapy.…”

Section: Resultsmentioning

confidence: 99%

Angiogenesis, Anti-Tumor, and Anti-Metastatic Activity of Novel α-Substituted Hetero-Aromatic Chalcone Hybrids as Inhibitors of Microtubule Polymerization

Sun

Wang

et al. 2021

Front. Chem.

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A library of new heteroaromatic ring-linked chalcone analogs were designed and synthesized of these, compound 7m with α-CH3 substitution and bearing a benzofuran ring, displaying the most potent activity, with IC50 values of 0.07–0.183 µM against three cancer cells. Its low cytotoxicity toward normal human cells and strong potency on drug-resistant cells revealed the possibility for cancer therapy. It also could moderately inhibit in vitro tubulin polymerization with an IC50 value of 12.23 µM, and the disruption of cellular architecture in MCF-7 cells was observed by an immunofluorescence assay. Cellular-based mechanism studies elucidated that 7m arrested the cell cycle at the G2/M phase and induced apoptosis by regulating the expression levels of caspases and PARP protein. Importantly, the compound 7 m was found to inhibit HUVEC tube formation, migration, and invasion in vitro. In vivo assay showed that 7m could effectively destroy angiogenesis of zebrafish embryos. Furthermore, our data suggested that treatment with 7m significantly reduced MCF-7 cell metastasis and proliferation in vitro and in zebrafish xenograft. Collectively, this work showed that chalcone hybrid 7m deserves further investigation as dual potential tubulin polymerization and angiogenesis inhibitor.

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“…The antiproliferative activities of target compounds against A549, PC-3, HepG2, and NRK-52E were evaluated using the MTT assay according to the previous articles 46 , 47 . Briefly, the assay was measured at 490 nm by an Infinite ® M200 PRO multimode Plate Readers (Tecan Group Ltd., Switzerland).…”

Section: Methodsmentioning

confidence: 99%

Discovery of facile amides-functionalized rhodanine-3-acetic acid derivatives as potential anticancer agents by disrupting microtubule dynamics

Zhou

Liu

Meng³

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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Microtubule dynamics are crucial for multiple cell functions, and cancer cells are particularly sensitive to microtubule-modulating agents. Here, we describe the design and synthesis of a series of ( Z )-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)- N -phenylacetamide derivatives and evaluation of their microtubule-modulating and anticancer activities in vitro . Proliferation assays identified I 20 as the most potent of the antiproliferative compounds, with 50% inhibitory concentrations ranging from 7.0 to 20.3 µM with A549, PC-3, and HepG2 human cancer cell lines. Compound I 20 also disrupted cancer A549 cell migration in a concentration-dependent manner. Immunofluorescence microscopy, transmission electron microscopy, and tubulin polymerisation assays suggested that compound I 20 promoted protofilament assembly. In support of this possibility, computational docking studies revealed a strong interaction between compound I 20 and tubulin Arg β 369, which is also the binding site for the anticancer drug Taxol. Our results suggest that ( Z )-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)- N -phenylacetamide derivatives could have utility for the development of microtubule-stabilising therapeutic agents.

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Design, synthesis, antitumor activities and biological studies of novel diaryl substituted fused heterocycles as dual ligands targeting tubulin and katanin

Cited by 26 publications

References 35 publications

Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity

Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity

Angiogenesis, Anti-Tumor, and Anti-Metastatic Activity of Novel α-Substituted Hetero-Aromatic Chalcone Hybrids as Inhibitors of Microtubule Polymerization

Discovery of facile amides-functionalized rhodanine-3-acetic acid derivatives as potential anticancer agents by disrupting microtubule dynamics

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