Anti-Proliferative and Cytoprotective Activity of Aryl Carbamate and Aryl Urea Derivatives with Alkyl Groups and Chlorine as Substituents

Abstract

Natural cytokinines are a promising group of cytoprotective and anti-tumor agents. In this research, we synthesized a set of aryl carbamate, pyridyl urea, and aryl urea cytokinine analogs with alkyl and chlorine substitutions and tested their antiproliferative activity in MDA-MB-231, A-375, and U-87 MG cell lines, and cytoprotective properties in H2O2 and CoCl2 models. Aryl carbamates with the oxamate moiety were selectively anti-proliferative for the cancer cell lines tested, while the aryl ureas were inactive. In the cytoprotection studies, the same aryl carbamates were able to counteract the CoCl2 cytotoxicity by 3–8%. The possible molecular targets of the aryl carbamates during the anti-proliferative action were the adenosine A2 receptor and CDK2. The obtained results are promising for the development of novel anti-cancer therapeutics.

New Hybrid Ethylenediurea (EDU) Derivatives and Their Phytoactivity

“…New EDU derivatives ( I – IX ) were obtained using known methods (according to Figure 2 ) from 2-imidazolidinone with an aminoethyl substituent by interaction with various aryl isocyanates in the presence of triethylamine in anhydrous acetonitrile, as described in [ 26 , 27 , 28 ]. The main physicochemical characteristics of compounds ( I – IX ) are given in the Supplementary Materials .…”

“…Arylureas N -[2-(2-oxoimidazolidin-1-yl)ethyl]- N ′-(3-chlorophenyl)urea ( I ), N -[2-(2- oxoimidazolidin-1-yl)ethyl]- N ′-(3,4-dichlorophenyl)urea ( II ), N -[2-(2-oxoimidazolidin-1-yl)ethyl ]- N ′-(3-chlorophenyl)urea ( III ), and N -[2-(2-oxo- imidazolidin-l-yl)ethyl]- N ′-phenylurea (IX) were synthesized earlier [ 27 , 28 ]. EDU derivatives N -[2-(2-oxoimidazolidin-1-yl)ethyl]- N ′-(4-tolyl)urea ( IV ), N -[2-(2-oxoimidazolidin-1-yl)ethyl]- N ′-(2,4-dimethylphenyl)urea ( V ), N -[2-(2-oxoimidazolidin-1-yl)ethyl]- N ′-(2,6-dimethylphenyl)urea ( VI ), N -[2-(2-oxoimidazolidin-1-yl)ethyl]- N ′-(4-methoxyphenyl)urea ( VII ), and N -[2-(2-oxoimidazolidin-1-yl)ethyl]- N ′-(2-ethylphenyl)urea ( VIII ) were obtained using the known method (according to Figure 2 ) from 2-imidazolidinone with an aminoethyl substituent by interaction with various arylisocyanates in the presence of triethylamine in anhydrous acetonitrile (see Supplementary Materials , Figures S1–S10 ).…”

Anti-Proliferative and Cytoprotective Activity of Ethylenediurea Derivatives with Alkyl and Oxygen-containing Groups as Substituents

“…Among phytohormones, cytokinins and their derivatives are particularly noteworthy due to their anticancer [7,10], antiproliferative activity [9,11], and immunomodulatory properties [10,12]. The first attempt to enhance the activity of cytokinins was the synthesis of their ribosides.…”

“…In crops, it mainly acts as a protective agent against the damaging effects of ozone and increases the phytotoxicity of many herbicides that are degraded in plants by oxygenases. A set of aryl carbamate and aryl urea EDU analogs with chlorine substitutions were synthesized and tested on antiproliferative activity in MDA-MB-231, A-375, and U-87 MG cell lines, and cytoprotective properties in H2O2 and CoCl2 models [11,19,20]. Aryl carbamates with the oxamate moiety were anti-proliferative for some cancer cell lines, while the aryl ureas were inactive.…”

“…In the cytoprotection studies, all the derivatives displayed only little or no activity. The possible molecular targets of aryl carbamates' anti-proliferative action may be the adenosine A2 receptor and CDK2 [11]. However, the observed anti-cancer and cytoprotective activity was rather low (about 30% decrease in cell proliferation at the concentration of the substances of 100 μM), and thus a search for a more active derivatives of this kind seems to be an interesting task.…”