ChemInform Abstract: Reaction of Mixed Anhydrides with Imines: Synthesis of 7‐Halogeno‐ and 7‐Azido‐5‐thia‐1‐azabicyclo(4.2.0)octan‐8‐ones and 7‐Halogeno‐ and 7‐ Azido‐5‐oxa‐1‐azabicyclo(4.2.0)octan‐8‐ones.

Cooke, Ellen; Walsh, O. M.; Meegan, Mary J.

doi:10.1002/chin.199522061

Cited by 1 publication

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“…Ketenes are usually formed in situ by a reaction of acyl halides with tertiary amines. However, 2-azetidinones are also directly accessible from imines and carboxylic acids via mixed anhydrides [65], using activating agents such as methoxymethylene-N,N-dimethyliminium salt, [66], the Vilsmeier reagent, the Mukaiyama reagent and triphosgene [67]. 3-Chloro-3-thioaryl-β-lactams, obtained by the chlorination of 3-thioaryl-β-lactams with sulfuryl chloride, are reported as suitable substrates for Lewis acid catalysed nucleophilic substitution reactions [68].…”

Section: Chemistrymentioning

confidence: 99%

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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