title: Synthesis, structure elucidation and identification of antiproliferative activities of a novel class of thiophene bioisosteres bearing the privileged 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-one scaffold.
abstract: The straightforward and practical synthesis route and remarkable antitumour activities in vitro of a novel class of thiophene bioisosteres (10-18) are disclosed. These molecules were obtained with good overall yields via the reaction of 1-aryl-2-hydrazonoimidazolidine hydroiodides with ethyl 2-oxo-2-(2-thienyl)acetate in the presence of triethylamine in refluxing DMF/methanol mixture. All the synthesized compounds proved to be markedly effective against human tumour cells: A549, HeLa, T47D and TOV112D and more cytotoxic than pemetrexed against A549, HeLa and T47D cells. Among these strongly antiproliferative active molecules, the disclosed three thiophene bioisosteres (11, 17 and 18) are proposed as the most promising anticancer lead structures for the rational design of more selective antitumour agents because they proved to be markedly lower cytotoxic towards normal than tumour cells. Results from the bioassay based on a double fluorochrome staining were worthy to be described because they provide a clue to the mode of action of one (18) of the most promising anticancer lead structures of the series.
authors.affiliation: Chair and Department of Medical Chemistry, Medical University, 4A Chodźki Street, 20-093 Lublin, Poland. Electronic address: malgorzata.sztanke@umlub.pl.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Sztanke
authors.affiliation: Department of Biology and Genetics, Medical University, 4A Chodźki Street, 20-093 Lublin, Poland.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Rzymowska
authors.affiliation: Laboratory of Bioorganic Synthesis and Analysis, Chair and Department of Medical Chemistry, Medical University, 4A Chodźki Street, 20-093 Lublin, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Sztanke
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D000068437:Pemetrexed / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology; D014227:Triazines / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D013876:Thiophenes; D014227:Triazines; D000068437:Pemetrexed
keywords: Agent-mediated necrosis; BrdUrd-based immunoassay; Cytotoxicity; Isosteric replacement; Lead structures; Thiophene bioisosteres