Synthesis and Biological Evaluation of S-, O- and Se-Containing Dispirooxindoles

Abstract

A series of novel S-, O- and Se-containing dispirooxindole derivatives has been synthesized using 1,3-dipolar cycloaddition reaction of azomethine ylide generated from isatines and sarcosine at the double C=C bond of 5-indolidene-2-chalcogen-imidazolones (chalcogen was oxygen, sulfur or selenium). The cytotoxicity of these dispiro derivatives was evaluated in vitro using different tumor cell lines. Several molecules have demonstrated a considerable cytotoxicity against the panel and showed good selectivity towards colorectal carcinoma HCT116 p53+/+ over HCT116 p53−/− cells. In particular, good results have been obtained for LNCaP prostate cell line. The performed in silico study has revealed MDM2/p53 interaction as one of the possible targets for the synthesized molecules. However, in contrast to selectivity revealed during the cell-based evaluation and the results obtained in computational study, no significant p53 activation using a reporter construction in p53wt A549 cell line was observed in a relevant concentration range.

Spirooxindole: A Versatile Biologically Active Heterocyclic Scaffold

“…Dispirooxindoles 73 were obtained through a cycloaddition reaction of 5-indolidene-2-chalcogen-imidazolones 72 with azmethine ylide (obtained from the condensation of sarcosine and paraformaldehyde) in refluxing toluene ( Scheme 20 ). Compound 73 with R = Cl, R’ = 4-MeOC 6 H 4 , X = S revealed considerable antiproliferative properties against HCT116 p53 +/+ and HCT116 p53 −/− CC 50 = 1.95, 2.35 μM, respectively [ 39 ].…”

Diffusion mixing with a volatile tertiary amine as a very efficient technique for 1,3-dipolar cycloaddition reactions proceeding via dehydrohalogenation of stable precursors of reactive dipoles

“…1,3-Dipolar cycloaddition is an important class of organic reactions that makes it possible to obtain five-membered cycles of various structural types with high atom economy and chemoselectivity. [1][2][3][4][5] Among the known 1,3-dipoles, nitrile oxides and nitrile imines are widely used intermediates in the synthesis of functionalized five-membered heterocycles. [6][7][8][9][10] The addition of these dipoles to the double CQC bonds often proceeds selectively under mild conditions [11][12][13] and can be used for modifications of both simple alkenes and complex polyfunctional molecules.…”

Women in Bioorganic Chemistry

“…The interest in the design and synthesis of novel anticancer therapeutics is also present in the manuscript by Beloglazina and co-workers from Moscow, Russia, who reported the synthesis of a series of S-, O-and Se-containing dispirooxoindoles through 1,3-dipolar cycloaddition of azomethine ylides, assayed their cytotoxicity against different tumor cell lines and performed an in silico study to rationalize the results [7]. The group of Simone and co-workers from Callaghan, Australia, reported the synthesis, glycosidase inhibition and anticancer properties of highly chlorinated benzamide analogues bearing a boronpinacolate ester group, with the perspective to use them in boron neutron capture therapy (BNCT) [8].…”