Synthesis and biological evaluation of novel shikonin-benzo[b]furan derivatives as tubulin polymerization inhibitors targeting the colchicine binding site

Shao, Yong; Yin, Yong; Lian, Baoping; Leng, Jiafu; Xia, Yuan‐Zheng; Kong, Ling‐Yi

doi:10.1016/j.ejmech.2020.112105

Cited by 31 publications

(28 citation statements)

References 31 publications

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“…Finally, we investigated the effect of 5 on the cell cycle. It has been reported that shikonin derivatives are able to bind to tubulin and, therefore, lead to cell cycle arrest [43,61]. Also, in the case of 2, we found a cell cycle arrest in different types of melanoma cell lines [14].…”

Section: Chemicalssupporting

confidence: 60%

Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives

Kretschmer

Hüfner

Durchschein

et al. 2021

IJMS

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Melanoma is the deadliest form of skin cancer and accounts for about three quarters of all skin cancer deaths. Especially at an advanced stage, its treatment is challenging, and survival rates are very low. In previous studies, we showed that the constituents of the roots of Onosma paniculata as well as a synthetic derivative of the most active constituent showed promising results in metastatic melanoma cell lines. In the current study, we address the question whether we can generate further derivatives with optimized activity by synthesis. Therefore, we prepared 31, mainly novel shikonin derivatives and screened them in different melanoma cell lines (WM9, WM164, and MUG-Mel2 cells) using the XTT viability assay. We identified (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclopropyl-2-oxoacetate as a novel derivative with even higher activity. Furthermore, pharmacological investigations including the ApoToxGloTM Triplex assay, LDH assay, and cell cycle measurements revealed that this compound induced apoptosis and reduced cells in the G1 phase accompanied by an increase of cells in the G2/M phase. Moreover, it showed hardly any effects on the cell membrane integrity. However, it also exhibited cytotoxicity against non-tumorigenic cells. Nevertheless, in summary, we could show that shikonin derivatives might be promising drug leads in the treatment of melanoma.

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Section: Chemicalssupporting

confidence: 60%

Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives

Kretschmer

Hüfner

Durchschein

et al. 2021

IJMS

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“…In the cellular microtubule system, microtubule formation is a dynamic equilibrium related to the polymerisation and depolymerisation of a, b-tubulin heterodimers 5 . Disrupting the tubulin dynamics equilibrium blocks the cell division at mitosis and thus resulting in the cell cycle arrest at metaphase, which leads to cell death 6,7 . Moreover, cancer cells are more in the division phase than normal cells, which means that they are more prone to anti-tubulin agents 8 .…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors

Wang

Liu

Fan

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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A novel series of thiazole-naphthalene derivatives as tubulin polymerisation inhibitors were designed, synthesised, and evaluated for the anti-proliferative activities. The majority of the tested compounds exhibited moderate to potent antiproliferative activity on the MCF-7 and A549 cancer cell lines. Among them, compound 5b was found to be the most active compound with IC 50 values of 0.48 ± 0.03 and 0.97 ± 0.13 lM. Moreover, mechanistic studies revealed that 5b significantly inhibited tubulin polymerisation with an IC 50 value of 3.3 mM, as compared to the standard drug colchicine (IC 50 ¼ 9.1 lM). Further cellular mechanism studies elucidated that 5b arrested the cell cycle at G2/M phase and induced apoptosis in MCF-7 cancer cells. Molecular modelling study indicated that 5b binds well to the colchicine binding site of tubulin. In summary, these results suggest that 5b represents a promising tubulin polymerisation inhibitor worthy of further investigation as potential anticancer agents.

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“…We assembled a dataset of 851 compounds tested as Tub-Mts inhibitors and with reported bioactivity in different cancer cell lines [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. All compounds were retrieved from original and review articles and patents over a period of 15 years (2005–2020).…”

Section: Methodsmentioning

confidence: 99%

Tubulin Inhibitors: A Chemoinformatic Analysis Using Cell-Based Data

2021

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Inhibiting the tubulin-microtubules (Tub-Mts) system is a classic and rational approach for treating different types of cancers. A large amount of data on inhibitors in the clinic supports Tub-Mts as a validated target. However, most of the inhibitors reported thus far have been developed around common chemical scaffolds covering a narrow region of the chemical space with limited innovation. This manuscript aims to discuss the first activity landscape and scaffold content analysis of an assembled and curated cell-based database of 851 Tub-Mts inhibitors with reported activity against five cancer cell lines and the Tub-Mts system. The structure–bioactivity relationships of the Tub-Mts system inhibitors were further explored using constellations plots. This recently developed methodology enables the rapid but quantitative assessment of analog series enriched with active compounds. The constellations plots identified promising analog series with high average biological activity that could be the starting points of new and more potent Tub-Mts inhibitors.

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Synthesis and biological evaluation of novel shikonin-benzo[b]furan derivatives as tubulin polymerization inhibitors targeting the colchicine binding site

Cited by 31 publications

References 31 publications

Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives

Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives

Design, synthesis and biological evaluation of novel thiazole-naphthalene derivatives as potential anticancer agents and tubulin polymerisation inhibitors

Tubulin Inhibitors: A Chemoinformatic Analysis Using Cell-Based Data

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