Pharmaceutical and Safety Profile Evaluation of Novel Selenocompounds with Noteworthy Anticancer Activity

Abstract

Prior studies have reported the potent and selective cytotoxic, pro-apoptotic, and chemopreventive activities of a cyclic selenoanhydride and of a series of selenoesters. Some of these selenium derivatives demonstrated multidrug resistance (MDR)-reversing activity in different resistant cancer cell lines. Thus, the aim of this study was to evaluate the pharmaceutical and safety profiles of these selected selenocompounds using alternative methods in silico and in vitro. One of the main tasks of this work was to determine both the physicochemical properties and metabolic stability of these selenoesters. The obtained results proved that these tested selenocompounds could become potential candidates for novel and safe anticancer drugs with good ADMET parameters. The most favorable selenocompounds turned out to be the phthalic selenoanhydride (EDA-A6), two ketone-containing selenoesters with a 4-chlorophenyl moiety (EDA-71 and EDA-73), and a symmetrical selenodiester with a pyridine ring and two selenium atoms (EDA-119).

Organic selenocompounds: are they the panacea for human illnesses?

“…Like Ebselen, SeTal cannot contribute significantly to the inorganic selenium pool at least in human coronary artery endothelial or smooth muscle cells. Another recent example of the importance of using at least some of the suggested and other additional in silico methodologies can be found in Marc et al 268 These authors followed a hierarchical and rational approach, where nearly a dozen in vitro bioactive selenoesters 267,363–365 were selected for detailed pharmaceutical and safety studies. The in vitro and in silico battery of tests included the determination of water solubility, stability of the selenoesters in alkaline and acidic media, membrane permeability (using the parallel artificial membrane permeability assay or PAMPA test), the in silico metabolic stability simulation (MetaSite) and in vitro metabolic stability after incubating the selenoesters with human microsomes.…”

“…The preliminary safety of the selenoesters is based on a small modification of the classical mutagenicity test of Ames, using bacteria. 268…”

“…The preliminary safety of the selenoesters is based on a small modification of the classical mutagenicity test of Ames, using bacteria. 268 Many efforts need to be made to clarify the mechanism of action of OSeCs, and the identification of their physicochemical properties, metabolites and/or active molecules is a critical step that is missing for the majority of compounds tested in vivo. In the past, the in vivo studies with vertebrates were considered acceptable as preliminary steps in the evaluation of pharmacologically or toxicologically active new compounds; however, now from an ethical point of view, this indicated a violation of vertebrate rights.…”

Reversal of Multidrug Resistance by Symmetrical Selenoesters in Colon Adenocarcinoma Cells

“…Among selenocarbonyl compounds, selenoesters have proved to be effective efflux pump inhibitors and chemosensitizer agents in various in vitro studies [ 25 ]. The underlying molecular mechanisms of selenoesters in MDR cancer cells are not fully known yet, but the available lines of evidence suggest that it may be related to the ability of the selenoesters to be hydrolyzed, releasing reactive selenium species (RSeS) that can be involved in intracellular redox reactions with thiols, free radicals, and reactive oxygen species [ 20 , 26 ]. The generation of RSeS could push this oxidative stress level in cancer cells above the critical redox threshold, leading to apoptotic or necrotic cell death [ 27 ].…”

Novel Selenoesters as a Potential Tool in Triple-Negative Breast Cancer Treatment

“…The group of organoselenium compounds consists of more than 10 chemical classes—including selenoesters [ 12 ]. These compounds are characterized by rapid action as a result of their molecule hydrolysis in the intracellular environment and release of reactive Se-containing forms with anticancer activity [ 13 ]. In the course of research performed by many teams all over the world, it was shown that selenoesters possess high cytotoxic potential, even in nanomolar concentrations, against many types of cancers (lung, colorectal, hepatic, pancreatic, ovarian, cervical, skin) [ 14 , 15 , 16 , 17 ].…”