Dispirooxindoles Based on 2-Selenoxo-Imidazolidin-4-Ones: Synthesis, Cytotoxicity and ROS Generation Ability

Abstract

A regio- and diastereoselective synthesis of two types of dispiro derivatives of 2-selenoxoimidazolidin-4-ones, differing in the position of the nitrogen atom in the central pyrrolidine ring of the spiro-fused system—namely, 2-selenoxodispiro[imidazolidine-4,3′-pyrrolidine-2′,3″-indoline]-2″,5-diones (5a-h) and 2-senenoxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-diones (6a-m)—were developed based on a 1,3-dipolar cycloaddition of azomethine ylides generated from isatin and sarcosine or formaldehyde and sarcosine to 5-arylidene or 5-indolidene-2-selenoxo-tetrahydro-4H-imidazole-4-ones. Selenium-containing dispiro indolinones generally exhibit cytotoxic activity near to the activity of the corresponding oxygen and sulfur-containing derivatives. Compounds 5b, 5c, and 5e demonstrated considerable in vitro cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) test (concentration of compounds that caused 50% death of cells (CC50) 7.6–8.7 μM) against the A549 cancer cell line with the VA13/A549 selectivity index 5.2–6.9 and compound 6e—against the MCF7 cancer cell line (CC50 20.6 μM, HEK293T/A549 selectivity index 1.6); some compounds (5 and 6) increased the level of intracellular reactive oxygen species (ROS) in the experiment on A549 and PC3 cells using platinized carbon nanoelectrode. The tests for p53 activation for compounds 5 and 6 on the transcriptional reporter suggest that the investigated compounds can only have an indirect p53-dependent mechanism of action. For the compounds 5b, 6b, and 6l, the ROS generation may be one of the significant mechanisms of their cytotoxic action.

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

“…The reaction proceeded smoothly in ether at room temperature and furnished the desired intermediates with 61-98% yield. In contrast to the compounds of such structural type, described in [24,26], this article presents dispiro derivatives with aryl and non-carcass alkyl substituents at N(3) position and with different exocyclic chalcogen atoms (oxygen, sulfur or selenium) in imidazolone fragment. Some results of cytotoxic action mechanisms studying for synthesized compounds are also presented, as well as the molecular docking data to evaluate their possible binding affinity toward MDM2.…”

“…Selenohydantoin derivatives 6g, 6h, 6q, 6r may be readily obtained from sarcosine, paraformaldehyde and the corresponding indolidene-selenohydantoins5g, 5h, 5q, 5r according to the modified method described in [26,34] (Scheme 3). .…”

“…. Selenohydantoin derivatives 6g, 6h, 6q, 6r may be readily obtained from sarcosine, paraformaldehyde and the corresponding indolidene-selenohydantoins 5g, 5h, 5q, 5r according to the modified method described in [26,34] (Scheme 3). O-containing derivatives 9 were synthesized from S-alkylated derivatives 7 of corresponding thiohydantoins 3 (Scheme 4).…”

“…We have recently described a series of novel spiro-oxindoles containing thiohydantoin [23][24][25], selenohydantoin [26] or hydantoin [25,27] moieties, presumably having an anticancer effect by inhibiting the p53/MDM2 protein interaction; one such derivative has recently successfully completed preclinical trials as a drug for the treatment of colorectal cancer [28]. The most active compounds of this type have shown cytotoxicity in the 4-11 µm range on cancer cell lines HepG2, MCF-7, SiHa and HCT116, [23], and some p53 activation by Western blotting (see Supplementary Information, Figure S1).…”

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.…”