Synthesis, Biological Evaluation, and Molecular Docking of Arylpyridines as Antiproliferative Agent Targeting Tubulin

He, Jiapeng; Zhang, Mao; Tang, Lv; Liu, Jie; Zhong, Jiahong; Wang, Wenya; Wang, Haitao; Li, Xiaofang; Zhou, Zhong‐Zhen

doi:10.1021/acsmedchemlett.0c00278

Cited by 15 publications

(5 citation statements)

References 28 publications

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“…The 3-chloro β-lactam 10n was next evaluated in the HL-60 cell line (acute myeloid leukaemia), the colon adenocarcinoma cell line SW480 and also in the HT-29 human colorectal adenocarcinoma cell line. 10n demonstrated a potent effect with IC 50 values of 10, 37 and 631 nM, respectively, that compared favourably with the IC 50 values for CA-4 we obtained in these cell lines of 2 nM (HL-60), 3 nM (SW480) and 4.165 mM (HT-29), respectively (Table 5) and are in agreement with the reported values for CA-4 in MCF-7 and human breast cancer and leukaemia cell lines [74,82,83]. The corresponding values for 10e in these cell lines were 161 nM (HL-60), 55 nM (SW480) and 135 nM (HT-29).…”

Section: Antiproliferative Activity Of Selected β-Lactam Compounds In Multiple Myeloma (U266) Acute Myeloid Leukaemia (Hl60) and Colon Casupporting

confidence: 90%

“…a IC 50 values are half maximal inhibitory concentrations required to block the growth stimulation of MCF-7, HL-60, U266, SW480 and HT-29 cells. Values represent the mean (SEM error values 10 −6 ) for three experiments performed in triplicate at 72 h.b The IC 50 value obtained for CA-4 in this assay is in good agreement with the reported value (see refs75,82,83). c nd: not determined.…”

supporting

confidence: 83%

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Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4

et al. 2021

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Antimitotic drugs that target tubulin are among the most widely used chemotherapeutic agents; however, the development of multidrug resistance has limited their clinical activity. We report the synthesis and biological properties of a series of novel 3-chloro-β-lactams and 3,3-dichloro-β-lactams (2-azetidinones) that are structurally related to the tubulin polymerisation inhibitor and vascular targeting agent, Combretastatin A-4. These compounds were evaluated as potential tubulin polymerisation inhibitors and for their antiproliferative effects in breast cancer cells. A number of the compounds showed potent activity in MCF-7 breast cancer cells, e.g., compound 10n (3-chloro-4-(3-hydroxy-4-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) and compound 11n (3,3-dichloro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one), with IC50 values of 17 and 31 nM, respectively, and displayed comparable cellular effects to those of Combretastatin A-4. Compound 10n demonstrated minimal cytotoxicity against non-tumorigenic HEK-293T cells and inhibited the in vitro polymerisation of tubulin with significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 10n caused a mitotic catastrophe by targeting tubulin. In addition, compound 10n promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2 and Mcl-1. Molecular docking was used to explore the potential molecular interactions between novel 3-chloro-β-lactams and the amino acid residues of the colchicine binding active site cavity of β-tubulin. Collectively, these results suggest that 3-chloro-2-azetidinones, such as compound 10n, could be promising lead compounds for further clinical anti-cancer drug development.

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Section: Antiproliferative Activity Of Selected β-Lactam Compounds In Multiple Myeloma (U266) Acute Myeloid Leukaemia (Hl60) and Colon Casupporting

confidence: 90%

supporting

confidence: 83%

Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4

et al. 2021

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“…3) exhibited significant antiproliferative activity against A549, MCF-7 and SKOV3 cells with IC50 values of 5.62 μg/mL, 1.14 μg/mL and 5.50 μg/mL respectively. He et al designed and synthesized a series of novel benzo[d]imidazole, benzo[d]thiazole, and benzo[d]oxazole derivatives as tubulin inhibitors [60]. Among them, the optimal compound 50 (Fig.…”

Section: Trimethoxyphenyl or Its Analogue Moiety As The Crucial Pharm...mentioning

confidence: 99%

An Update on the Recent Advances and Discovery of Novel Tubulin Colchicine Binding Inhibitors

Weng

Zhu

et al. 2023

Future Med. Chem.

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Microtubules, formed by α- and β-tubulin heterodimer, are considered as a major target to prevent the proliferation of tumor cells. Microtubule-targeted agents have become increasingly effective anticancer drugs. However, due to the relatively sophisticated chemical structure of taxane and vinblastine, their application has faced numerous obstacles. Conversely, the structure of colchicine binding site inhibitors (CBSIs) is much easier to be modified. Moreover, CBSIs have strong antiproliferative effect on multidrug-resistant tumor cells and have become the mainstream research orientation of microtubule-targeted agents. This review focuses mainly on the recent advances of CBSIs during 2017–2022, attempts to depict their biological activities to analyze the structure–activity relationships and offers new perspectives for designing next generation of novel CBSIs.

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“… 19 For example, a series of substituted pyridine compounds have been reported as tubulin polymerisation inhibitors ( 7–9 , Figure 1 ). 20–22 …”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and biological evaluation of novel diarylpyridine derivatives as tubulin polymerisation inhibitors

Yang

Wang

Shi

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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A set of novel diarylpyridines as anti-tubulin agents were designed, synthesised using a rigid pyridine as a linker to fix the cis -orientation of ring-A and ring-B. All of the target compounds were evaluated for their in vitro antiproliferative activities. Among them, 10t showed remarkable antiproliferative activities against three cancer cell lines (HeLa, MCF-7 and SGC-7901) in sub-micromolar concentrations. Consistent with its potent antiproliferative activity, 10t also displayed potent anti-tubulin activity. Cellular mechanism investigation elucidated 10t disrupted the cellular microtubule structure, arrested cell cycle at G2/M phase and induces apoptosis. Molecular modelling studies showed that 10t could bind to the colchicine binding site on microtubules. These results provide motivation and further guidance for the development of new CA-4 analogues.

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Synthesis, Biological Evaluation, and Molecular Docking of Arylpyridines as Antiproliferative Agent Targeting Tubulin

Cited by 15 publications

References 28 publications

Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4

Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4

An Update on the Recent Advances and Discovery of Novel Tubulin Colchicine Binding Inhibitors

Design, synthesis and biological evaluation of novel diarylpyridine derivatives as tubulin polymerisation inhibitors

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