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

Małgorzata Anna Marć,Gniewomir Latacz,Gabriella Spengler,Carmen Sanmartín,Agata Doroz-Płonka,Enrique Domínguez-Álvarez,Jadwiga Handzlik

doi:10.3390/pharmaceutics14020367

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).

Highlights

Despite of being poisonous at high doses, selenium is an essential trace element for living organisms [1]: it is involved in major metabolic pathways and crucial physiological functions, such as antioxidant defense and membrane stabilizing activity
They were found to be able to inhibit bacterial biofilm formation [22] and the bacterial efflux pumps involved in bacterial resistance to antibiotics [21]. These Se compounds inhibited the ABCB1 efflux pump, commonly involved in the resistance developed by multidrug-resistant cancer cells towards chemotherapy [19]. These results suggested that this phthalic selenoanhydride and these selenoesters are very promising scaffolds in medicinal chemistry, the pharmaceutical profile and safety of which are discussed in this paper
It was observed that the solubility results obtained by the means of the SwissADME program were similar to those found with the OSIRIS computational method

Summary

Introduction

Despite of being poisonous at high doses, selenium is an essential trace element for living organisms [1]: it is involved in major metabolic pathways and crucial physiological functions, such as antioxidant defense and membrane stabilizing activity. Selenium plays a redox gatekeeper role in the detoxification and chemopreventive pathways in the human body [1,2]. Selenium is a micronutrient with potential applications in the treatment or prevention of specific diseases, including cardiovascular disorders, thyroid and neurodegenerative diseases, depression, acute pancreatitis (AP), viral infections (such as HIV), and cancer [4,5]. In all these pharmaceutical applications, the gap between toxic and therapeutic doses is narrow [6].

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