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

• Main Authors: Vladimir K. Novotortsev, Maxim E. Kukushkin, Viktor A. Tafeenko, Dmitry A. Skvortsov, Marina A. Kalinina, Roman V. Timoshenko, Nelly S. Chmelyuk, Liliya A. Vasilyeva, Boris N. Tarasevich, Petr V. Gorelkin, Alexander S. Erofeev, Alexander G. Majouga, Nikolai V. Zyk, Elena K. Beloglazkina
• Format: Article
• Language: English
• Published: MDPI AG 2021-03-01
• Series: International Journal of Molecular Sciences
• Subjects: selenohydantoins; spiro compounds; indolinones; azomethine ylides; cytotoxicity; ROS generation
• Online Access: https://www.mdpi.com/1422-0067/22/5/2613

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 (<b>5a-h</b>) and 2-senenoxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-diones (<b>6a-m</b>)—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 <b>5b</b>, <b>5c</b>, and <b>5e</b> 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 <b>6e</b>—against the MCF7 cancer cell line (CC₅₀ 20.6 μM, HEK293T/A549 selectivity index 1.6); some compounds (<b>5</b> and <b>6</b>) 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 <b>5</b> and <b>6</b> on the transcriptional reporter suggest that the investigated compounds can only have an indirect p53-dependent mechanism of action. For the compounds <b>5b</b>, <b>6b</b>, and <b>6l</b>, the ROS generation may be one of the significant mechanisms of their cytotoxic action.