Abstract
A series of spiro[isoindole-1,5-isoxazolidin]-3(2H)-ones has been synthesized by 1,3-dipolar cycloaddition of N-benzylnitrone with isoindolin-3-methylene-1-ones. The regio- and stereoselectivity of the process have been rationalized by computational methods. The obtained compounds show cytotoxic properties and antiproliferative activity in the range of 9–22 μM. Biological tests suggest that the antitumor activity could be linked to the inhibition of the protein–protein p53-MDM2 interaction. Docking measurements support the biological data.
Highlights
The p53 tumor suppressor protein is a transcriptional factor that plays a key role in the regulation of several cellular processes, including apoptosis, DNA repair, and angiogenesis [1,2,3,4]
The synthetic scheme towards the construction of the spiro[isoxazolidin-isoindolinone] system 3 starts from isoindolinones 2 which have been synthesized, as reported [35], by Pd-catalyzed aminocarbonylation-N-heterocyclization of 2-ethynylbenzamides 1
The best results have been obtained by performing the 1,3-dipolar cycloaddition in toluene at 110 °C for 4 h, under microwave irradiation: cycloadducts 6a–e have been isolated in 38–60% yield, as major isomers, together with isomers 7 as minor adducts and unreacted isoindolinones 2a–e mainly in E configuration (Scheme 2, Table 1)
Summary
The p53 tumor suppressor protein is a transcriptional factor that plays a key role in the regulation of several cellular processes, including apoptosis, DNA repair, and angiogenesis [1,2,3,4]. The MTS assay [46,47] showed a significant reduction in cellular viability in all cancer cell lines treated with compounds 6a–f at concentrations ranging from 1 to 100 μM, when compared with respective controls.
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