Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones

Malebari, Azizah M.; Morales, Gabriela Duffy; Twamley, Brendan; Fayne, Darren; Khan, Mohemmed Faraz; McLoughlin, Eavan; O’Boyle, Niamh M.; Zisterer, Daniela M.; Meegan, Mary J.

doi:10.3390/ph15091044

Cited by 8 publications

(5 citation statements)

References 89 publications

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“…Several researchers have tried to use four-membered ring β-lactam as a bridge in the CA-4; these derivatives showed potent antiproliferative and antimitotic activities [ 50 , 51 , 52 , 53 ], and compound St.8 ( Figure 4 ) showed significant cytotoxicity against MCF7 cancer cell lines with IC 50 values in nanomolar with significant in vitro inhibition of tubulin polymerization [ 54 ]. On the same core cycle, another group synthesized a series of (3-substituted 1,4-diaryl-2-azetidine) and compound St.9 ( Figure 4 ) was significantly the cell proliferation in IC 50 range 31-63 nM, as well as its tubulin polymerization inhibition’s IC 50 was around 3.5 µM.…”

Section: Combretastatin A-4 Analoguesmentioning

confidence: 99%

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy

Hawash

2022

Biomolecules

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Cancer accounts for numerous deaths each year, and it is one of the most common causes of death worldwide, despite many breakthroughs in the discovery of novel anticancer candidates. Each new year the FDA approves the use of new drugs for cancer treatments. In the last years, the biological targets of anticancer agents have started to be clearer and one of these main targets is tubulin protein; this protein plays an essential role in cell division, as well as in intracellular transportation. The inhibition of microtubule formation by targeting tubulin protein induces cell death by apoptosis. In the last years, numerous novel structures were designed and synthesized to target tubulin, and this can be achieved by inhibiting the polymerization or depolymerization of the microtubules. In this review article, recent novel compounds that have antiproliferation activities against a panel of cancer cell lines that target tubulin are explored in detail. This review article emphasizes the recent developments of tubulin inhibitors, with insights into their antiproliferative and anti-tubulin activities. A full literature review shows that tubulin inhibitors are associated with properties in the inhibition of cancer cell line viability, inducing apoptosis, and good binding interaction with the colchicine binding site of tubulin. Furthermore, some drugs, such as cabazitaxel and fosbretabulin, have been approved by FDA in the last three years as tubulin inhibitors. The design and development of efficient tubulin inhibitors is progressively becoming a credible solution in treating many species of cancers.

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Section: Combretastatin A-4 Analoguesmentioning

confidence: 99%

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy

Hawash

2022

Biomolecules

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“…Although the compounds were biologically evaluated as racemates, it was interesting that the 3 S ,4 R enantiomer of each compound was found to be ranked at lower energy in the docking study than the corresponding 3 R ,4 S enantiomer. We had previously reported stereochemical selectivity in docking energy calculated for related β-lactam compounds [ 54 , 105 ]. However, a very small difference was observed in the cellular efficacy of this series of compounds in the modelling study (e.g., IC 50 values in the range 10–61 nM), so it would not be expected to see a large difference in ranking.…”

Section: Resultsmentioning

confidence: 99%

“…CA-4 analogues containing the β-lactam heterocycle have been reported [ 46 , 47 , 48 ], while chiral azetidin-2-ones disrupt tubulin polymerization and suppress angiogenesis [ 49 , 50 , 51 ]. We previously reported the antimitotic properties of novel β-lactam analogues of CA-4, which were synthesised using optimised Staudinger and Reformatsky chemistry, with preferred trans stereochemistry for the C3 and C4 ring substituents [ 52 , 53 , 54 ]. These β-lactam compounds are distinguished by introduction of the 3,4,5-trimethoxyphenyl ring A (as in CA-4), required for activity, a β-lactam ring as the linking group to replace the double bond of CA-4 (thus preventing E/Z isomerisation in aqueous conditions) and a substituted aryl ring at C-4 as ring B.…”

Section: Introductionmentioning

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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“…Based on the availability of a 3D protein structure and prior knowledge of target protein biological function(s), CADD is divided into two main approaches: structure-based drug design (SBDD) and ligand-based drug design (LBDD). SBDD approaches utilize protein 3D structures to design compounds that are anticipated to bind with high affinity to the target protein . In the absence of a protein 3D structure, LBDD is a widely used approach.…”

Section: Introductionmentioning

confidence: 99%

“…SBDD approaches utilize protein 3D structures to design compounds that are anticipated to bind with high affinity to the target protein. 7 In the absence of a protein 3D structure, LBDD is a widely used approach. The knowledge of known active compounds’ chemical and structural characteristics required for binding to the target is utilized in LBDD approaches.…”

Section: Introductionmentioning

confidence: 99%

DataPype: A Fully Automated Unified Software Platform for Computer-Aided Drug Design

Khan,

Kandwal,

Fayne

2023

ACS Omega

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With the advent of computer-aided drug design (CADD), traditional physical testing of thousands of molecules has now been replaced by target-focused drug discovery, where potentially bioactive molecules are predicted by computer software before their physical synthesis. However, despite being a significant breakthrough, CADD still faces various limitations and challenges. The increasing availability of data on small molecules has created a need to streamline the sourcing of data from different databases and automate the processing and cleaning of data into a form that can be used by multiple CADD software applications. Several standalone software packages are available to aid the drug designer, each with its own specific application, requiring specialized knowledge and expertise for optimal use. These applications require their own input and output files, making it a challenge for nonexpert users or multidisciplinary discovery teams. Here, we have developed a new software platform called DataPype, which wraps around these different software packages. It provides a unified automated workflow to search for hit compounds using specialist software. Additionally, multiple virtual screening packages can be used in the one workflow, and if different ways of looking at potential hit compounds all predict the same set of molecules, we have higher confidence that we should make or purchase and test the molecules. Importantly, DataPype can run on computer servers, speeding up the virtual screening for new compounds. Combining access to multiple CADD tools within one interface will enhance the early stage of drug discovery, increase usability, and enable the use of parallel computing.

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Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones

Cited by 8 publications

References 89 publications

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy

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

DataPype: A Fully Automated Unified Software Platform for Computer-Aided Drug Design

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