title: Chalcogen containing heterocyclic scaffolds: New hybrids with antitumoral activity.
abstract: In this work, 27 novel hybrid derivatives containing diverse substituents with chalcogen atoms (selenium or sulfur) and several active heterocyclic scaffolds have been synthesized. Compounds were tested against two human cancer cells lines (MCF7 and PC-3) and a normal human mammary epithelial cell line (184B5) in order to determine their activity and selectivity against malignant cells. Ten compounds showed GI50 values below 10 μM in at least one of the cancer cell lines and six of them exhibited a selectivity index higher than 9. In general, selenium-containing compounds were more active than their corresponding sulfur analogs but we found some thiocyanate derivatives with comparable or higher activity and selectivity. Among the different substituents, the seleno- and thio-cyanate groups showed the most promising results. On the basis of their potent activity and high selectivity index, compounds 7e and 8f (containing a thiocyanate and a selenocyanate group, respectively) were selected for further biological evaluation. Both the compounds induced caspase-dependent cell death and cell cycle arrest in G2/M phase. In addition, these compounds do not violate any of the Lipinski's Rule of Five and thus possess good potential to become drugs, compound 7e being particularly promising.
authors.affiliation: Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008 Pamplona, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Alcolea
authors.affiliation: Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008 Pamplona, Spain; Department of Pharmacology, Penn State Hershey Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Plano
authors.affiliation: Department of Health Sciences, Public University of Navarra, Avda. Barañain s/n, E-31008 Pamplona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Encío
authors.affiliation: Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008 Pamplona, Spain.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Palop
authors.affiliation: Department of Pharmacology, Penn State Hershey Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Department of Organic and Pharmaceutical Chemistry, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, E-31008 Pamplona, Spain. Electronic address: sanmartin@unav.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sanmartín
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018011:Chalcogens / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D018011:Chalcogens; D006571:Heterocyclic Compounds
keywords: Apoptosis; Cell cycle arrest; Chalcogen; Cytotoxicity; Selenium