Cyano-and ketone-containing selenoesters as multi-target compounds 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.The study was supported by the projects SZTE ÁOK-KKA 2018/270-62-2 of the University of Szeged, Faculty of Medicine and GINOP-2.3.2-15-2016-00038 (Hungary); and Consejo Superior de Investigaciones Científicas (CSIC, Spain, project LINKA20285). This research was funded by VISEGRAD FUND, grant number 22010090; and by the mobility project from the Czech Ministry of Education, Youth and Sports INTER-COST, grant number LTC19007. This article is based upon work from COST Action 17104 , supported by COST (European Cooperation in Science and Technology), (http://www.cost.eu, accessed on 17 September 2021). The study was supported also by two cultural associations: “Trevinca” and “Iniciativas Ropelanas”

Efflux pump inhibition by symmetric selenoesters on colon adenocarcinoma cells

The development of resistance to chemotherapy in tumour cells is often due to altered membrane transport, such as the overexpression of ABCB1 (P-glycoprotein). Previously, selenium and its derivatives have been reported as antiproliferative, cytotoxic compounds that can also reduce drug resistance in tumour cells, trigger apoptotic events and enhance synergistically the anticancer activity of chemotherapy drugs such as doxorubicin. This work aims to elucidate how the symmetrical selenoesters exert their anticancer effect on sensitive and resistant human colon adenocarcinoma cells expressing ABCB1 protein. MTT assay was applied to assess both the antiproliferative and cytotoxic effects of the compounds on sensitive and resistant colon adenocarcinoma and normal embryonic lung fibroblast cells. A flow cytometry based assay which determines the accumulation of rhodamine 123 was used to assess the efflux pump inhibitory activity of the tested selenoesters. Finally, annexin V-FITC staining was used to determine the apoptosis-inducing effect of the most promising derivatives. Furthermore, the interaction of the compounds with doxorubicin was assessed by checkerboard combination assay and the type of interaction was calculated by Calcusyn software. Methyl ketone-containing compounds (EDAG-1, -5, -8) showed the most potent antiproliferative and cytotoxic effects. Out of them, EDAG-5 was the one that had the most synergistic interaction with doxorubicin. On the other hand, the methyloxycarbonylmethyl- and the methylcyano selenoesters had a very low cytotoxic activity on the normal MRC-5 fibroblast cell line. Methyl ketone- and methylcyano-selenoesters (EDAG-7, -10, 11) were more potent ABCB1 inhibitors than the reference compound verapamil. Finally, a methyl ketone selenoester (EDAG-1) was an effective inducer of apoptosis in the resistant Colo 320 cell line. The biological activities observed are comparable or higher than the ones determined in previous works. Thus, it seems that the inclusion of symmetric centres in these selenocompounds may favour (or at least retain) the biological activity. Based on these results, it can be concluded that these compounds (or derivatives containing these symmetrical elements) could be interesting scaffolds for future research in medicinal chemistry

Inhibition–Disruption of Candida glabrata Biofilms: Symmetrical Selenoesters as Potential Anti-Biofilm Agents

Candida glabrata is one of the most prevalent pathogenic Candida species in dental plaque on tooth surfaces. Candida biofilms exhibit an enhanced resistance against most antifungal agents. Thus, the development of alternative more potent and effective antimicrobials is required to overcome this resistance. In this study, three novel fluorinated derivatives and nine selenoester compounds were screened as novel antifungal and antibiofilm agents against C. krusei, C. parapsilosis, and C. glabrata (N = 81 dental isolates). C. glabrata strains were susceptible only to fluorinated compounds while C. krusei, C. parapsilosis, and C. glabrata were susceptible to the action of the selenoesters. The evaluated symmetrical selenoester compounds presented very good antifungal activity against all the tested C. glabrata dental isolates (1–4 μg/mL of minimum inhibitory concentration-MIC). The most active compound (Se-5) was able to inhibit and disperse C. glabrata biofilms. These results demonstrated that selenoesters may be novel and promising biocide agents against C. glabrata clinical dental isolates

Inhibition–disruption of Candida glabrata biofilms: Symmetrical selenoesters as potential anti-biofilm agents

Candida glabrata is one of the most prevalent pathogenic Candida species in dental plaque on tooth surfaces. Candida biofilms exhibit an enhanced resistance against most antifungal agents. Thus, the development of alternative more potent and effective antimicrobials is required to overcome this resistance. In this study, three novel fluorinated derivatives and nine selenoester compounds were screened as novel antifungal and antibiofilm agents against C. krusei, C. parapsilosis, and C. glabrata (N = 81 dental isolates). C. glabrata strains were susceptible only to fluorinated compounds while C. krusei, C. parapsilosis, and C. glabrata were susceptible to the action of the selenoesters. The evaluated symmetrical selenoester compounds presented very good antifungal activity against all the tested C. glabrata dental isolates (1–4 µg/mL of minimum inhibitory concentration-MIC). The most active compound (Se-5) was able to inhibit and disperse C. glabrata biofilms. These results demonstrated that selenoesters may be novel and promising biocide agents against C. glabrata clinical dental isolates.This research was funded by Consejo Superior de Investigaciones Científicas (CSIC), grant numbers COOPB20237 (A.B.) and 201780I027 (E.D.

Biofilm Eradication by Symmetrical Selenoesters for Food-Borne Pathogens

© 2020 by the authors.Infections caused by Salmonella species and Staphylococcus aureus represent major health and food industry problems. Bacteria have developed many strategies to resist the antibacterial activity of antibiotics, leading to multidrug resistance (MDR). The over-expression of drug efflux pumps and the formation of biofilms based on quorum sensing (QS) can contribute the emergence of MDR. For this reason, the development of novel effective compounds to overcome resistance is urgently needed. This study focused on the antibacterial activity of nine symmetrical selenoesters (Se-esters) containing additional functional groups including oxygen esters, ketones, and nitriles against Gram-positive and Gram-negative bacteria. Firstly, the minimum inhibitory concentrations of the compounds were determined. Secondly, the interaction of compounds with reference antibiotics was examined. The efflux pump (EP) inhibitory properties of the compounds were assessed using real-time fluorimetry. Finally, the anti-biofilm and quorum sensing inhibiting effects of selenocompounds were determined. The methylketone and methyloxycarbonyl selenoesters were the more effective antibacterials compared to cyano selenoesters. The methyloxycarbonyl selenoesters (Se-E2 and Se-E3) showed significant biofilm and efflux pump inhibition, and a methyloxycarbonyl selenoester (Se-E1) exerted strong QS inhibiting effect. Based on results selenoesters could be promising compounds to overcome bacterial MDR.The study was supported by the projects SZTE ÁOK-KKA 2018/270-62-2 of the University of Szeged, Faculty of Medicine and GINOP-2.3.2-15-2016-00038 (Hungary). M.N. was supported by EFOP 3.6.3-VEKOP-16-2017-00009. E.D-A. was supported by ‘Iniciativas Ropelanas’ and ‘Asociación Cultural Trevinca’, two associations from Zamora (Spain), that promote cancer research.Peer reviewe

Demographic, clinical, and functional determinants of antithrombotic treatment in patients with nonvalvular atrial fibrillation

Altres ajuts: Alliance Bristol-Myers Squibb/Pfizer.Background: This study assessed the sociodemographic, functional, and clinical determinants of antithrombotic treatment in patients with nonvalvular atrial fibrillation (NVAF) attended in the internal medicine setting. Methods: A multicenter, cross-sectional study was conducted in NVAF patients who attended internal medicine departments for either a routine visit (outpatients) or hospitalization (inpatients). Results: A total of 961 patients were evaluated. Their antithrombotic management included: no treatment (4.7%), vitamin K antagonists (VKAs) (59.6%), direct oral anticoagulants (DOACs) (21.6%), antiplatelets (6.6%), and antiplatelets plus anticoagulants (7.5%). Permanent NVAF and congestive heart failure were associated with preferential use of oral anticoagulation over antiplatelets, while intermediate-to high-mortality risk according to the PROFUND index was associated with a higher likelihood of using antiplatelet therapy instead of oral anticoagulation. Longer disease duration and institutionalization were identified as determinants of VKA use over DOACs. Female gender, higher education, and having suffered a stroke determined a preferential use of DOACs. Conclusions: This real-world study showed that most elderly NVAF patients received oral anticoagulation, mainly VKAs, while DOACs remained underused. Antiplatelets were still offered to a proportion of patients. Longer duration of NVAF and institutionalization were identified as determinants of VKA use over DOACs. A poor prognosis according to the PROFUND index was identified as a factor preventing the use of oral anticoagulation