title: Chemopreventive and antioxidant activity of 6-substituted imidazo[2,1-b]thiazoles.
abstract: The synthesis of new imidazo[2,1-b]thiazoles bearing phenolic groups is reported. These compounds and some previously described analogs were evaluated as antioxidant agents with three chemical model systems, and cancer chemopreventive potential was examined by inhibition of NO production, TNF-α activated NFκB activity, and aromatase activity, as well as induction of QR1 and RXRE binding. Two of the test compounds, 9 and 12, displayed promising activity by inhibiting iNOS, NFκB and aromatase in dose-dependent manner, with IC50 values in low micromolar range. The same compounds activated QR1 in a bifunctional manner. When incubated with human liver microsomes, the active compounds were further hydroxylated on the parent ring system, suggesting the next logical step in the development of these promising leads will entail synthetic production of metabolites followed by additional assessment of biological activity.
authors.affiliation: Dipartimento di Farmacia e Biotecnologie FaBiT, Università di Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Andreani
authors.forename: Alberto
authors.initials: A
authors.lastname: Leoni
authors.forename: Alessandra
authors.initials: A
authors.lastname: Locatelli
authors.forename: Rita
authors.initials: R
authors.lastname: Morigi
authors.forename: Mirella
authors.initials: M
authors.lastname: Rambaldi
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Cervellati
authors.forename: Emanuela
authors.initials: E
authors.lastname: Greco
authors.forename: Tamara P
authors.initials: TP
authors.lastname: Kondratyuk
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: Ke
authors.initials: K
authors.lastname: Huang
authors.forename: Richard B
authors.initials: RB
authors.lastname: van Breemen
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047072:Aromatase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D019556:COS Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D016588:Anticarcinogenic Agents; D000975:Antioxidants; D047072:Aromatase Inhibitors; D001381:Azepines; D007093:Imidazoles; D016328:NF-kappa B; D013844:Thiazoles; C576326:imidazo(1,2-a)(1,4)diazepin-76H-one; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II
keywords: 2,2-diphenyl-1-picrylhydrazyl; 3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyltetrazolium bromide; AhR; Antioxidants; BDE; BR; Bond Dissociation Enthalpies; Briggs–Rauscher; Chemopreventive agents; DPPH; IR; Imidazo[2,1-b]thiazoles; L-N(G)-monomethyl arginine citrate; L-NMMA; MTT; NFκB; Polyphenols; QR1, NAD(P)H; RAC; RNS; ROS; RXR; RXRE; Relative Antioxidant Capacity; SRB; SRM; TEAC; TNF; TPCK; Trolox Equivalent Antioxidant Activity; aryl hydrocarbon receptor; iNOS; inducible nitric oxide synthase; induction ratio; nuclear factor kappa beta; quinone reductase 1; reactive nitrogen species; reactive oxygen species; retinoid X receptor; retinoid X receptor response element; selected reaction monitoring; sulforhodamine B; tosyl phenylalanyl chloromethyl ketone; tumor necrosis factor