title: Synthesis and biological evaluation of imidazolo[2,1-b]benzothiazole derivatives, as potential p53 inhibitors.
abstract: Since activation of p53 in response to cytotoxic stress may have proapoptotic or protective effects depending on the nature of the injury, inhibitors of p53 may have therapeutic interest as modulators of chemotherapy toxicity or efficacy. In an attempt to identify novel p53 inhibitors, a quality collection of compounds structurally related to pifithrin-β were designed and synthesized as potential inhibitors of p53. The biochemical and biological evaluations supported that compounds of the tetrahydrobenzothiazole series were inhibitors of the p53 transcriptional activity and were effective in enhancing paclitaxel-induced apoptosis. In contrast, in spite of the increased cytotoxic potency, selected compounds of the benzothiazole series were not able to modulate the transcriptional activity of p53, as indicated by lack of change of p21 expression. The therapeutic interest of the compounds of the former series in combination with taxanes was confirmed in a human tumor xenograft model.
authors.affiliation: Chemistry Laboratory, Agricultural University of Athens, Athens, Greece.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Christodoulou
authors.forename: Francesco
authors.initials: F
authors.lastname: Colombo
authors.forename: Daniele
authors.initials: D
authors.lastname: Passarella
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ieronimo
authors.forename: Valentina
authors.initials: V
authors.lastname: Zuco
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.forename: Franco
authors.initials: F
authors.lastname: Zunino
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D052160:Benzothiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D014050:Toluene / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin