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Molecules 2017, 22(8), 1288; doi:10.3390/molecules22081288

Novel Methylselenoesters as Antiproliferative Agents

1
Department of Organic and Pharmaceutical Chemistry, Faculty of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain
2
Oncology and Hematology Section, IdiSNA, Navarra Institute for Health Research, Irunlarrea 3, E-31008 Pamplona, Spain
3
Division of Biochemistry, Department of Medical Biochemistry and Biophysics (MBB), Karolinska Institutet, SE-171 77 Stockholm, Sweden
4
Department of Health Sciences, Public University of Navarra, Avda. Barañain s/n, E-31008 Pamplona, Spain
*
Author to whom correspondence should be addressed.
Received: 29 June 2017 / Revised: 26 July 2017 / Accepted: 28 July 2017 / Published: 2 August 2017
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Abstract

Selenium (Se) compounds are potential therapeutic agents in cancer. Importantly, the biological effects of Se compounds are exerted by their metabolites, with methylselenol (CH3SeH) being one of the key executors. In this study, we developed a new series of methylselenoesters with different scaffolds aiming to modulate the release of CH3SeH. The fifteen compounds follow Lipinski’s Rule of Five and with exception of compounds 1 and 14, present better drug-likeness values than the positive control methylseleninic acid. The compounds were evaluated to determine their radical scavenging activity. Compound 11 reduced both DPPH and ABTS radicals. The cytotoxicity of the compounds was evaluated in a panel of five cancer cell lines (prostate, colon and lung carcinoma, mammary adenocarcinoma and chronic myelogenous leukemia) and two non-malignant (lung and mammary epithelial) cell lines. Ten compounds had GI50 values below 10 μM at 72 h in four cancer cell lines. Compounds 5 and 15 were chosen for further characterization of their mechanism of action in the mammary adenocarcinoma cell line due to their similarity with methylseleninic acid. Both compounds induced G2/M arrest whereas cell death was partially executed by caspases. The reduction and metabolism were also investigated, and both compounds were shown to be substrates for redox active enzyme thioredoxin reductase. View Full-Text
Keywords: methylselenoester; methylselenol release; cytotoxicity; cell cycle arrest; cell death; thioredoxin reductase methylselenoester; methylselenol release; cytotoxicity; cell cycle arrest; cell death; thioredoxin reductase
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Díaz-Argelich, N.; Encío, I.; Plano, D.; Fernandes, A.P.; Palop, J.A.; Sanmartín, C. Novel Methylselenoesters as Antiproliferative Agents. Molecules 2017, 22, 1288.

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