Combined Acylselenourea-Diselenide Structures: New Potent and Selective Antitumoral Agents as Autophagy Activators.

Autor: Garnica P; University of Navarra, Faculty of Pharmacy and Nutrition, Department of Organic and Pharmaceutical Chemistry, Irunlarrea 1, E-31008 Pamplona, Spain.; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008 Pamplona, Spain., Encío I; Department of Health Sciences, Public University of Navarra, Avda. Barañain s/n, E-31008 Pamplona, Spain., Plano D; University of Navarra, Faculty of Pharmacy and Nutrition, Department of Organic and Pharmaceutical Chemistry, Irunlarrea 1, E-31008 Pamplona, Spain.; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008 Pamplona, Spain., Palop JA; University of Navarra, Faculty of Pharmacy and Nutrition, Department of Organic and Pharmaceutical Chemistry, Irunlarrea 1, E-31008 Pamplona, Spain.; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008 Pamplona, Spain., Sanmartín C; University of Navarra, Faculty of Pharmacy and Nutrition, Department of Organic and Pharmaceutical Chemistry, Irunlarrea 1, E-31008 Pamplona, Spain.; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008 Pamplona, Spain.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Mar 13; Vol. 9 (4), pp. 306-311. Date of Electronic Publication: 2018 Mar 13 (Print Publication: 2018).
DOI: 10.1021/acsmedchemlett.7b00482
Abstrakt: A series of 16 new diselenide-acylselenourea conjugates have been designed following the fragment-based drug strategy. Compound in vitro cytotoxic potential was evaluated against six human cancer cell lines and two nonmalignant derived cell lines with the aim of determining their potency and selectivity. Nine derivatives exhibited GI 50 values under 10 μM in at least four cancer cell lines. A clear gap situated phenyl substitution over heterocyclic moieties in terms of selectivity. Among carbocyclic compounds, derivatives 2 and 7 significantly inhibited cell growth of breast adenocarcinoma cells with GI 50 values of 1.30 and 0.15 nM, respectively, with selectivity indexes 12 and 121 times higher than those obtained for doxorubicin. Preliminary mechanistic studies indicated that compounds 2 and 7 induce cell cycle arrest and autophagy-dependent cell death evidenced by the blockage of cell death with pretreatment with wortmannin or chloroquine and confirmed by the upregulation of the markers Beclin1 and LC3B in MCF-7 cells.
Competing Interests: The authors declare no competing financial interest.
Databáze: MEDLINE
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