3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

Wang, Shu; Malebari, Azizah M.; Greene, T. F.; O’Boyle, Niamh M.; Fayne, Darren; Nathwani, Seema M.; Twamley, Brendan; McCabe, Thomas; Keely, Niall O.; Zisterer, Daniela M.; Meegan, Mary J.

doi:10.3390/ph12020056

Cited by 12 publications

(14 citation statements)

References 97 publications

(138 reference statements)

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“…Preliminary docking studies revealed that the vinyl substituent sits in the CBS. These results are promising for further development of the β-lactam structures as more stable analogues of CA-4 [72].…”

Section: -Vinyl Substituted β-Lactamsmentioning

confidence: 85%

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

2020

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It is over 50 years since the discovery of microtubules, and they have become one of the most important drug targets for anti-cancer therapies. Microtubules are predominantly composed of the protein tubulin, which contains a number of different binding sites for small-molecule drugs. There is continued interest in drug development for compounds targeting the colchicine-binding site of tubulin, termed colchicine-binding site inhibitors (CBSIs). This review highlights CBSIs discovered through diverse sources: from natural compounds, rational design, serendipitously and via high-throughput screening. We provide an update on CBSIs reported in the past three years and discuss the clinical status of CBSIs. It is likely that efforts will continue to develop CBSIs for a diverse set of cancers, and this review provides a timely update on recent developments.

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Section: -Vinyl Substituted β-Lactamsmentioning

confidence: 85%

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

2020

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“…The crystal structures of the imines 8h and 8i demonstrated the E configuration of the imines (Supplementary Materials Tables S1 and S13). The novel 3-(prop-1-en-2-yl)azetidin-2-ones (9a-p, 9r) were obtained by reaction of imines 8a-8r with 3,3-dimethylacryloyl chloride using the Staudinger reaction conditions with triethylamine as the base [60][61][62] (Scheme 1; Scheme 2). The β-lactam compounds (9t-v), were also prepared containing the 3,4,5-trimethoxyphenyl substituent (ring A) at the C-4 position, together with structurally related β-lactams 9w and 9x (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

Antiproliferative and Tubulin-Destabilising Effects of 3-(Prop-1-en-2-yl)azetidin-2-Ones and Related Compounds in MCF-7 and MDA-MB-231 Breast Cancer Cells

et al. 2023

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A series of novel 3-(prop-1-en-2-yl)azetidin-2-one, 3-allylazetidin-2-one and 3-(buta-1,3-dien-1-yl)azetidin-2-one analogues of combretastatin A-4 (CA-4) were designed and synthesised as colchicine-binding site inhibitors (CBSI) in which the ethylene bridge of CA-4 was replaced with a β-lactam (2-azetidinone) scaffold. These compounds, together with related prodrugs, were evaluated for their antiproliferative activity, cell cycle effects and ability to inhibit tubulin assembly. The compounds demonstrated significant in vitro antiproliferative activities in MCF-7 breast cancer cells, particularly for compounds 9h, 9q, 9r, 10p, 10r and 11h, with IC50 values in the range 10–33 nM. These compounds were also potent in the triple-negative breast cancer (TBNC) cell line MDA-MB-231, with IC50 values in the range 23–33 nM, and were comparable with the activity of CA-4. The compounds inhibited the polymerisation of tubulin in vitro, with significant reduction in tubulin polymerization, and were shown to interact at the colchicine-binding site on tubulin. Flow cytometry demonstrated that compound 9q arrested MCF-7 cells in the G2/M phase and resulted in cellular apoptosis. The antimitotic properties of 9q in MCF-7 human breast cancer cells were also evaluated, and the effect on the organization of microtubules in the cells after treatment with compound 9q was observed using confocal microscopy. The immunofluorescence results confirm that β-lactam 9q is targeting tubulin and resulted in mitotic catastrophe in MCF-7 cells. In silico molecular docking supports the hypothesis that the compounds interact with the colchicine-binding domain of tubulin. Compound 9q is a novel potent microtubule-destabilising agent with potential as a promising lead compound for the development of new antitumour agents.

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“…19 Wang et al designed and synthesized three series of 3dienyl--lactams as inhibitors targeting a binding site of colchicine. 20 The imines 16 were accessed via butadienyl ketene generated in situ by the action of sorbic acid and suitable base in dichloromethane to afford 3-(buta-1,3dien-1-yl)azetidin-2-ones 17 (Table 5). Derivatives 17 also exhibited in vitro antitumor activity against the MCF-7 breast cancer cell line, with IC 50 values of 23-33 nM.…”

Section: Review Synopenmentioning

confidence: 99%

“…Derivatives 17 also exhibited in vitro antitumor activity against the MCF-7 breast cancer cell line, with IC 50 values of 23-33 nM. 20 Scheme 3 [4+2] cycloaddition of butadienyl ketene 4 and 1,3-diazabuta-l,3-dienes 25…”

Section: Review Synopenmentioning

confidence: 99%

Butadienyl Ketene: An Unexplored Intermediate in Organic Synthesis

Mann,

Wahan,

Bhargava

et al. 2024

SynOpen

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Butadienyl ketene is a useful intermediate for its role as 2- components in cycloaddition reactions with a variety of substrate such as simple/conjugated imines and dienes. The current review article summarizes the different reports on the in-situ generation of butadienyl ketene and their cycloaddition reactions to afford different heterocyclic systems. The chemistry of butadienyl ketene is explored only for their [2+2] and [4+2] cycloaddition with a variety of imines and azadiene such as 1,3-diazabuta-1,3-dienes for the synthesis of four- and six-membered heterocycles respectively.

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3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

Cited by 12 publications

References 97 publications

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

Antiproliferative and Tubulin-Destabilising Effects of 3-(Prop-1-en-2-yl)azetidin-2-Ones and Related Compounds in MCF-7 and MDA-MB-231 Breast Cancer Cells

Butadienyl Ketene: An Unexplored Intermediate in Organic Synthesis

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