title: Dibenzo[1,4,5]thiadiazepine: a hardly-known heterocyclic system with neuroprotective properties of potential usefulness in the treatment of neurodegenerative diseases.
abstract: In this work we describe a new family of dibenzo[1,4,5]thiadiazepines (2-12) that showed an interesting in vitro biological profile, namely neuroprotective and antioxidant properties, as well as blockade of cytosolic calcium entry. They showed no cytotoxic effects and the majority were predicted as CNS-permeable compounds. In human neuroblastoma cells they displayed good neuroprotective properties against mitochondrial oxidative stress which, in many cases, almost reached the full protection (>90%) when compounds were incubated with cells 24 h before the addition of toxic stressors. In co-incubation conditions these figures were smaller, although some compounds maintained an interesting level of neuroprotection, higher than 50%. Four selected compounds (2, 5, 8, and 11) were found to be effective antioxidant agents by sequestering mitochondrial radical oxygen species (ROS). Moreover, compound 2 showed a remarkable calcium-channel modulating activity. The interest of these compounds is increased by the fact that dibenzo[1,4,5]thiadiazepine is a barely known structure that is not difficult to synthesize and presents very few described derivatives, opening a new and broad line of research in Medicinal Chemistry.
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Gema C
authors.initials: GC
authors.lastname: González-Muñoz
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Mariana P
authors.initials: MP
authors.lastname: Arce
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Pérez
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Villarroya
authors.affiliation: Instituto Teófilo Hernando and Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/Arzobispo Morcillo 4, 28029 Madrid, Spain.
authors.forename: Manuela G
authors.initials: MG
authors.lastname: López
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: sconde@iqm.csic.es.
authors.forename: Santiago
authors.initials: S
authors.lastname: Conde
authors.affiliation: Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/ Juan de la Cierva 3, 28006 Madrid, Spain. Electronic address: isabelrguez@iqm.csic.es.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
mesh_terms: D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013841:Thiazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D013841:Thiazepines; C000595939:dibenzo(1,4,5)thiadiazepine
keywords: Alzheimer's disease; Antioxidant; Calcium modulation; Dibenzo[1,4,5]thiadiazepines; Mitochondrial oxidative stress; Neuroprotection