Recent advances in trimethoxyphenyl (TMP) based tubulin inhibitors targeting the colchicine binding site

Li, Ling; Jiang, Shuhui; Li, Xiaoxun; Liu, Yao; Su, Jing; Chen, Jianjun

doi:10.1016/j.ejmech.2018.04.011

Cited by 176 publications

(109 citation statements)

References 93 publications

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“…Over the last decade, a variety of molecules bearing the trimethoxyphenyl moiety have been designed and synthesised as anticancer agents [13][14][15] . In addition, trimethoxyphenyl derivatives have enjoyed great success due to their potent chemical stability and pharmacokinetics for cancer treatment 16 . These above interesting findings led us to perform the molecular hybridisation strategy of biologically active sulfonamide, dithiocarbamate and trimethoxyphenyl fragments to generate a novel scaffold with the aim of studying the impact of such modification on their antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

Anticancer sulfonamide hybrids that inhibit bladder cancer cells growth and migration as tubulin polymerisation inhibitors

Liu

Zhang

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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Novel sulfonamide-dithiocarbamate hybrids were designed and synthesised via the molecular hybridisation strategy. Among them, compound 13d displayed a potent activity with IC 50 values of 0.9, 0.7, 1.9 and 2.6 µM against UM-UC-3, RT-112, RT4 and T24. Compound 13d inhibited the migration and regulated the migration-related markers (E-cadherin, N-cadherin, Vimentin, Snail and Slung) against RT-112 cells in a concentration dependent manner. By the tubulin polymerisation assay in vitro and immunostaining assay, compound 13d was identified as a novel tubulin polymerisation inhibitor. Intragastric administration of compound 13d could inhibit the growth of RT-112 cells in vivo in a xenograft mouse model with the low toxicity, indicating that it may be a leading candidate with antitumor properties to treat bladder cancer.

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Section: Introductionmentioning

confidence: 99%

Anticancer sulfonamide hybrids that inhibit bladder cancer cells growth and migration as tubulin polymerisation inhibitors

Liu

Zhang

et al. 2019

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…We were intrigued by the idea of studying the biological effects of replacing the carboxamido group at the 2-position of the 4,5,6,7-tetrahydrothieno [2,3-c]pyridine ring of compounds with general structure 2 with a 3 ,4 ,5 -trimethoxyanilino moiety to yield the 2-(3 ,4 ,5 -trimethoxyanilino)-3-cyano-6-methoxy/ ethoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridines 3a and 3b. Previous studies have shown that the 3,4,5-trimethoxyphenyl moiety is a pharmacophoric group that is an essential structural requirement for the anticancer effect of numerous inhibitors of tubulin polymerization, such as colchicine, combretastatin A-4 (CA-4), podophyllotoxin, and poly-methoxychalcone [49,50]. Starting from compounds 3a and 3b, additional analogues were also generated by modification of the 3-cyano function of the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine skeleton.…”

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confidence: 99%

Synthesis and Biological Evaluation of New Antitubulin Agents Containing 2-(3′,4′,5′-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine Scaffold

et al. 2020

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Two novel series of compounds based on the 4,5,6,7-tetrahydrothieno[2,3-c]pyridine and 4,5,6,7-tetrahydrobenzo[b]thiophene molecular skeleton, characterized by the presence of a 3 ,4 ,5 -trimethoxyanilino moiety and a cyano or an alkoxycarbonyl group at its 2-or 3-position, respectively, were designed, synthesized, and evaluated for antiproliferative activity on a panel of cancer cell lines and for selected highly active compounds, inhibition of tubulin polymerization, and cell cycle effects. We have identified the 2-(3 ,4 ,5 -trimethoxyanilino)-3-cyano-6-methoxycarbonyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine derivative 3a and its 6-ethoxycarbonyl homologue 3b as new antiproliferative agents that inhibit cancer cell growth with IC 50 values ranging from 1.1 to 4.7 µM against a panel of three cancer cell lines. Their interaction with tubulin at micromolar levels leads to the accumulation of cells in the G2/M phase of the cell cycle and to an apoptotic cell death. The cell apoptosis study found that compounds 3a and 3b were very effective in the induction of apoptosis in a dose-dependent manner. These two derivatives did not induce cell death in normal human peripheral blood mononuclear cells, suggesting that they may be selective against cancer cells. Molecular docking studies confirmed that the inhibitory activity of these molecules on tubulin polymerization derived from binding to the colchicine site.

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“…However, the clinical efficacy of the drugs is often limited by occurrence and evolution of resistance mechanisms that is further compounded by a narrow therapeutic index (Du et al., ; Gigant et al., ; Kavallaris, ; Perez, ; Wang, Chen, Miller, & Li, ; Wang et al., ). Recently, some colchicine binding tubulin inhibitors exhibit significant ability to overcome multidrug resistance (Bacher et al., ; Banerjee et al., ; Bueno et al., ; Cui et al., ; Dohle et al., ; Gangjee et al., ; Lauria et al., ; Li et al., ; Ohsumi et al., ; Pang et al., ; Suman et al., ). Even some drug candidates have already entered the clinical trial stage (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and biological evaluation of quinoxaline derivatives as tubulin polymerization inhibitors that elevate intracellular ROS and triggers apoptosis via mitochondrial pathway

et al. 2019

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A series of novel quinoxaline derivatives were synthesized and evaluated for their antiproliferative activity in three human cancer cell lines. Compound 12 exhibited the most potent antiproliferative activity with IC50 in the range of 0.19–0.51 μM. The compound inhibited tubulin polymerization and disrupted the microtubule network, leading to G2/M phase arrest. Furthermore, compound 12 induced ROS production and malfunction of mitochondrial membrane potential. Compound 12 led to cancer cells apoptosis in a dose‐dependent manner. Western blot analysis showed that compound 12 induced up‐regulation of p21 and affected the expression of cell cycle‐related proteins. The binding mode was also probed by molecular docking.

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Recent advances in trimethoxyphenyl (TMP) based tubulin inhibitors targeting the colchicine binding site

Cited by 176 publications

References 93 publications

Anticancer sulfonamide hybrids that inhibit bladder cancer cells growth and migration as tubulin polymerisation inhibitors

Anticancer sulfonamide hybrids that inhibit bladder cancer cells growth and migration as tubulin polymerisation inhibitors

Synthesis and Biological Evaluation of New Antitubulin Agents Containing 2-(3′,4′,5′-trimethoxyanilino)-3,6-disubstituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridine Scaffold

Synthesis and biological evaluation of quinoxaline derivatives as tubulin polymerization inhibitors that elevate intracellular ROS and triggers apoptosis via mitochondrial pathway

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