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

Vladimir K Novotortsev,Viktor A Tafeenko,Boris N Tarasevich,Alexander S Erofeev,Maxim E Kukushkin,Dmitry A Skvortsov,Liliya A Vasilyeva,Elena K Beloglazkina,Petr V Gorelkin,Nelly S Chmelyuk,Marina A Kalinina,Roman V Timoshenko,Alexander G Majouga,Nikolai V Zyk

doi:10.3390/ijms22052613

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; 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.

Highlights

IntroductionHydantoin and thiohydantoin derivatives containing the spiro-linked indolinone fragments showed significant cytotoxic activity in the in vitro experiments [1,2,3]
Taking into account that the variation of the exocyclic chalcogen substituent of the imidazolone fragment of dispiroimidazolones in the works cited above [1,2,4] did not lead to a significant change in cytotoxicity, and considering the fact that selenium-containing compounds are an attractive class of compounds in search for new cytotoxic anticancer agents [16,17,18,19], in this work, we present a further structural modification of spiro-linked 2-halcogen-imidazolone derivatives, introducing into their molecular structure C=Se groups
It may be noted that some organoselenium compounds are currently evaluated in clinics as anticancer drugs, including L-selenomethionine and

Summary

Introduction

Hydantoin and thiohydantoin derivatives containing the spiro-linked indolinone fragments showed significant cytotoxic activity in the in vitro experiments [1,2,3]. The most potent dispiro-thiohydantoins from this series exhibited an IC50 value in the range of. Taking into account that the variation of the exocyclic chalcogen substituent (oxygen or sulfur) of the imidazolone fragment of dispiroimidazolones in the works cited above [1,2,4] did not lead to a significant change in cytotoxicity, and considering the fact that selenium-containing compounds are an attractive class of compounds in search for new cytotoxic anticancer agents [16,17,18,19], in this work, we present a further structural modification of spiro-linked 2-halcogen-imidazolone derivatives, introducing into their molecular structure C=Se groups. It may be noted that some organoselenium compounds are currently evaluated in clinics as anticancer drugs, including L-selenomethionine and

Methods

Discussion

Conclusion