title: Hybrid molecules containing benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazole and alpha-bromoacryloyl moieties as potent apoptosis inducers on human myeloid leukaemia cells.
abstract: The synthesis and biological activity of a series of hybrids 1-5 prepared combining a benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazole and different benzoheterocyclic alpha-bromoacryloyl amides have been described and their structure-activity relationships discussed. All these hetero-bifunctional compounds were highly cytotoxic against the human myeloid leukaemia cell lines HL-60 and U937 (IC(50) 0.24-1.72microM), significantly superior to that of both alkylating units alone. In human myeloid leukaemia HL-60 cells we observed that these compounds suppress survival and proliferation by triggering morphological changes and internucleosomal DNA fragmentation characteristic of apoptotic cell death. The apoptosis induced by these compounds is mediated by caspase-3 activation and is also associated to an early release of cytochrome c from the mitochondria.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 Ferrara, Italy. rmr@unife.it
authors.forename: Romeo
authors.initials: R
authors.lastname: Romagnoli
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Maria Dora
authors.initials: MD
authors.lastname: Carrion
authors.forename: Olga
authors.initials: O
authors.lastname: Cruz-Lopez
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.forename: Francesca
authors.initials: F
authors.lastname: Fruttarolo
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
authors.forename: Jaime
authors.initials: J
authors.lastname: Bermejo
authors.forename: Francisco
authors.initials: F
authors.lastname: Estévez
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D053938:DNA Fragmentation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000473:pathology*; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D013830:Thiadiazoles