Cyano- and Ketone-Containing Selenoesters as Multi-Target Compounds against Resistant Cancers.

Nikoletta Szemerédi,Márta Nové,Annamária Kincses,Simona Dobiasová,Miguel Benito-Lama,Clotilde Sevilla-Hernández,Jitka Viktorová,Noemi Salardón-Jiménez,Giyaullah Habibullah,Francisco-Javier Alonso-Martínez,Gabriella Spengler,Enrique Domínguez-Álvarez

doi:10.3390/cancers13184563

Abstract

Simple SummaryThe search for novel anticancer agents has been the hot topic of interest in cancer research, due to the phenomenon of multidrug resistance (MDR) in cancer that can make cancer cells resistant to the current available chemotherapeutic agents. In this context, we have designed, synthesized, and biologically evaluated 15 novel selenoesters, with the aim to explore their activity against resistant cancer cell lines. Some of these described selenocompounds showed noteworthy cytotoxicity and selectivity, the ability to inhibit the ABCB1 efflux pump, the capacity to modulate the ATPase activity of this pump, the capability to trigger apoptotic events, the ability to interact in a synergistic manner with doxorubicin in resistant cancer cells, and the power to promote wound healing. Consequently, these results validate the design of these selenocompounds and justify further research to evaluate the possibilities of these compounds to be used in the future in the fight against resistant cancers.Fifteen selenocompounds, comprising of eight ketone-containing selenoesters (K1–K8, also known as oxoselenoesters) and seven cyano-containing selenoesters (N1–N7, known also as cyanoselenoesters), have been designed, synthesized, and evaluated as novel anticancer agents. These compounds are derivatives of previously reported active selenoesters and were prepared following a three-step one-pot synthetic route. The following evaluations were performed in their biological assessment: cytotoxicity determination, selectivity towards cancer cells in respect to non-cancer cells, checkerboard combination assay, ABCB1 inhibition and inhibition of ABCB1 ATPase activity, apoptosis induction, and wound healing assay. As key results, all the compounds showed cytotoxicity against cancer cells at low micromolar concentrations, with cyanoselenoesters being strongly selective. All of the oxoselenoesters, except K4, were potent ABCB1 inhibitors, and two of them, namely K5 and K6, enhanced the activity of doxorubicin in a synergistic manner. The majority of these ketone derivatives modulated the ATPase activity, showed wound healing activity, and induced apoptosis, with K3 being the most potent, with a potency close to that of the reference compound. To summarize, these novel derivatives have promising multi-target activity, and are worthy to be studied more in-depth in future works to gain a greater understanding of their potential applications against cancer.

Highlights

The occurrence of multidrug resistance (MDR) to chemotherapeutic drugs has become a significant challenge in cancer therapy
Cyanoselenoesters have been designed as a variation of the ones included in a previous patent of the group [18], with the same improvement aim of the activity showed by the initial cyanoselenoesters included in this patent
Seeing the noteworthy activity in previous works [15,16,17,18] shown by derivatives that contain halogens, we have considered different halogenated substituents, as well their polysubstitution, to determine which ones enhanced the biological effects

Summary

Introduction

The occurrence of multidrug resistance (MDR) to chemotherapeutic drugs has become a significant challenge in cancer therapy. (ABCB1), or the cluster of differentiation 243 (CD243)—was discovered in 1970 as a member of the ATP-binding cassette (ABC) transporter family [1,2] These ABC transporters fulfil physiological functions in the gastrointestinal tract, liver, and lungs. They are localized in different barriers that separate blood vessels from specific organs, such as the blood–brain barrier (BBB), the blood–cerebrospinal fluid (B-CSF), the blood–retina barrier (BRB), the blood–testis barrier (BTB), and in the placenta [3]. ABCB1 is comprised of two nucleotide-binding domains and 12 transmembrane domains which constitute a drug-binding pocket This transporter is a natural cell protective protein whose function is the removal of xenobiotic compound out of the cells, as this compound can be toxic for the cells [5,6]. It has been reported that ABCB1, together with the multidrug resistance-associated protein 1 (MRP1)/ATP Binding Cassette Subfamily C

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