Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis

Abstract

The utility of sterically hindered phenols (SHPs) in drug design is based on their chameleonic ability to switch from an antioxidant that can protect healthy tissues to highly cytotoxic species that can target tumor cells. This work explores the biological activity of a family of 45 new hybrid molecules that combine SHPs equipped with an activating phosphonate moiety at the benzylic position with additional urea/thiourea fragments. The target compounds were synthesized by reaction of iso(thio)cyanates with C-arylphosphorylated phenols containing pendant 2,6-diaminopyridine and 1,3-diaminobenzene moieties. The SHP/urea hybrids display cytotoxic activity against a number of tumor lines. Mechanistic studies confirm the paradoxical nature of these substances which combine pronounced antioxidant properties in radical trapping assays with increased reactive oxygen species generation in tumor cells. Moreover, the most cytotoxic compounds inhibited the process of glycolysis in SH-SY5Y cells and caused pronounced dissipation of the mitochondrial membrane of isolated rat liver mitochondria. Molecular docking of the most active compounds identified the activator allosteric center of pyruvate kinase M2 as one of the possible targets. For the most promising compounds, 11b and 17b, this combination of properties results in the ability to induce apoptosis in HuTu 80 cells along the intrinsic mitochondrial pathway. Cyclic voltammetry studies reveal complex redox behavior which can be simplified by addition of a large excess of acid that can protect some of the oxidizable groups by protonations. Interestingly, the re-reduction behavior of the oxidized species shows considerable variations, indicating different degrees of reversibility. Such reversibility (or quasi-reversibility) suggests that the shift of the phenol-quinone equilibrium toward the original phenol at the lower pH may be associated with lower cytotoxicity.

Recent Advances in Novel Compositions for Electrochemical Applications

“…I. Alabugin's research group in electrochemistry challenges the classical understanding of antioxidants and their properties [31]. By employing cyclic voltammetry with a semi-differential method, they unveiled new avenues in the quest for compounds that exhibit both antioxidant and anti-tumor properties.…”

“…This collection of articles presents extensive research and discoveries that leverage various morphologies of electrochemical compositions, emphasizing their multifunctional properties, such as advanced redox properties [24][25][26][27][28][29][30][31]. The published articles range from the drug design and synthesis of hybrids of sterically hindered phenols and diaryl ureas [31] to sophisticated studies on the enhancement of arc erosion resistance in AgCuO electrical contact materials [30].…”

“…This collection of articles presents extensive research and discoveries that leverage various morphologies of electrochemical compositions, emphasizing their multifunctional properties, such as advanced redox properties [24][25][26][27][28][29][30][31]. The published articles range from the drug design and synthesis of hybrids of sterically hindered phenols and diaryl ureas [31] to sophisticated studies on the enhancement of arc erosion resistance in AgCuO electrical contact materials [30]. Other notable topics include in-depth research on chemical and electrochemical reductions of monoiminoacenaphthenes [29], investigations on conductive mediators based on ferrocene functionalized phosphonium ionic liquids [26], and critical assessments of salt stress based on innovative electrochemical sensor detection methodologies [24].…”

Discovery of Di(het)arylmethane and Dibenzoxanthene Derivatives as Potential Anticancer Agents

“…In our previous studies, we found phenol derivatives that exhibit high cytotoxicity towards HuTu 80 and M-HeLa tumor cells due to the induction of apoptosis via mitochondrial pathway. An interesting feature of these compounds was a switch from redox protection to increased ROS production under the oxidative stress conditions typical for cancer cells [ 14 , 15 ]. Figure 1 A provides selected examples of phenol- and coumarin-containing biologically active substances, including anticancer drugs.…”