title: An unexpected Dimroth rearrangement leading to annelated thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidines with potent antitumor activity.
abstract: An unusual Dimroth rearrangement occurring in the reaction leading to annelated thieno[2,3-e][1,2,3]triazolo[1,5-a]pyrimidine core allowed the isolation of the linear isomer thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidine. By decorating the linear isomer with the same chains that improved the biological activity of the angular isomers, new annelated thieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidines were designed and synthesized. They were selected by the Developmental Therapeutics Program (DTP) of the National Cancer Institute (NCI) for the anticancer screening against a panel of 60 human tumor cell lines. The biological results showed that the new derivatives exhibited strong antiproliferative activity up to nanomolar concentration. In vivo screenings of the most active compound, the N-[2-(1H-imidazol-4-yl)ethyl]-4-(3-phenyl-10-oxo-4,10-dihydrobenzothieno[3,2-d][1,2,3]triazolo[1,5-a]pyrimidin-4-yl)butanamide, showed its low toxicity and high potency.
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche "STEBICEF", Sezione di Chimica Farmaceutica e Biologica, Università di Palermo, Via Archirafi 32, I-90123 Palermo, Italy. antonino.lauria@unipa.it
authors.forename: Antonino
authors.initials: A
authors.lastname: Lauria
authors.forename: Chiara
authors.initials: C
authors.lastname: Patella
authors.forename: Ilenia
authors.initials: I
authors.lastname: Abbate
authors.forename: Annamaria
authors.initials: A
authors.lastname: Martorana
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Almerico
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D014230:Triazoles; C586343:thieno(3,2-d)(1,2,3)triazolo(1,5-a)pyrimidine
keywords: Annelated thienotriazolopyrimidines; Anticancer agents; Developmental Therapeutics Program (DTP); Dimroth rearrangement; Domino reactions