An Improved Protocol for Synthesis of 3‐Substituted 5‐Arylidene‐2‐thiohydantoins: Two‐step Procedure Alternative to Classical Methods

Kuznetsova, O. Yu.; Antipin, R. L.; Udina, Anna V.; Krasnovskaya, Olga O.; Белоглазкина, Е. К.; Теренин, В. И.; Koteliansky, Victor; Зык, Н. В.; Majouga, Alexander G.

doi:10.1002/jhet.2464

Cited by 10 publications

(11 citation statements)

References 18 publications

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“…Ethyl isothiocyanoacetate was synthesized according to the described procedure. 71 The synthesis procedure was used in accordance with Kuznetsova et al 71 Ethyl isothiocyanoacetate (1 equiv) was added dropwise to a vigorously stirred solution of aniline in ∼10 mL of diethyl ether. The mixture was stirred until the white solid precipitate formed, and the solvent was evaporated under reduced pressure.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones

et al. 2020

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A series of 73 ligands and 73 of their Cu+2 and Cu+1 copper complexes with different geometries, oxidation states of the metal, and redox activities were synthesized and characterized. The aim of the study was to establish the structure–activity relationship within a series of analogues with different substituents at the N(3) position, which govern the redox potentials of the Cu+2/Cu+1 redox couples, ROS generation ability, and intracellular accumulation. Possible cytotoxicity mechanisms, such as DNA damage, DNA intercalation, telomerase inhibition, and apoptosis induction, have been investigated. ROS formation in MCF-7 cells and three-dimensional (3D) spheroids was proven using the Pt-nanoelectrode. Drug accumulation and ROS formation at 40–60 μm spheroid depths were found to be the key factors for the drug efficacy in the 3D tumor model, governed by the Cu+2/Cu+1 redox potential. A nontoxic in vivo single-dose evaluation for two binuclear mixed-valence Cu+1/Cu+2 redox-active coordination compounds, 72k and 61k, was conducted.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones

et al. 2020

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“…Arylidene-substituted selenohydantoins 3a-d and 5-indoliden-2-selenohydantoins 4a-m were obtained according to a modified procedure described for sulfur analogs [ 38 , 39 , 40 ] optimized for maximum yield of target compounds. The conditions for the synthesis of arylidene and indolinylidene-substituted selenohydantoins 3a-d and 4a-m were similar, except for the reaction time: during the compounds 3a-d preparations, the reactions were carried out for three h; for the preparation of compounds 4a-m , one h was enough.…”

Section: Resultsmentioning

confidence: 99%

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

Novotortsev

Kukushkin

Тафеенко

et al. 2021

IJMS

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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.

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“…The reaction proceeded smoothly in ether at room temperature and furnished the desired intermediates with 61-98% yield. Compounds 1a-j and 2a, b were then treated with equimolar amount of isatin or 5-chloroisatin to obtain indolidene-thiohydantoins 3a-x (Scheme 2), analogously to previously described reactions of substituted thioureas with aromatic aldehydes [30]. Finally, compounds 3a-xwere reacted with sarcosine and paraformaldehyde in toluene under reflux to obtain the desired substituted dispiroindolinones4a-x in a moderate-to-high yield.…”

Section: Chemistrymentioning

confidence: 94%

“…According to the-NMR spectroscopy data, the reactions in all cases proceed with the formation of single diastereomeric products 4a-x with the relative S*, R*-configuration, which was confirmed by the data of X-ray crystallographic analysis for the compound 4s (Figure 2). Compounds 1a-j and 2a, b were then treated with equimolar amount of isatin or 5-chloroisatin to obtain indolidene-thiohydantoins 3a-x (Scheme 2), analogously to previously described reactions of substituted thioureas with aromatic aldehydes [30]. Finally, compounds 3a-x were reacted with sarcosine and paraformaldehyde in toluene under reflux to obtain the desired substituted dispiroindolinones 4a-x in a moderate-to-high yield.…”

Section: Chemistrymentioning

confidence: 95%

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

et al. 2021

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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.

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An Improved Protocol for Synthesis of 3‐Substituted 5‐Arylidene‐2‐thiohydantoins: Two‐step Procedure Alternative to Classical Methods

Abstract: A novel method for the direct synthesis of 5-arylidene-2-thiohydantoins from thioureas and aromatic aldehydes in the presence of base in ethanol was developed. Application of this efficient method allowed preparing thiohydantoins, which are difficult to synthesis by traditional methods.

Cited by 10 publications

References 18 publications

Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones

Novel Copper-Containing Cytotoxic Agents Based on 2-Thioxoimidazolones

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

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

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