title: 2-Phenoxy-1,4-naphthoquinones: From a Multitarget Antitrypanosomal to a Potential Antitumor Profile.
abstract: A small library of 2-phenoxy-1,4-naphthoquinone and 2-phenoxy-1,4-anthraquinone derivatives was initially developed to optimize the antitrypanosomatid profile of the multitarget hit compound B6 (1). The whole series was evaluated against the three most important human trypanosomatid pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani), and two compounds (14 and 21) showed good activity, despite a concomitant mammalian cytotoxicity. Furthermore, a subset also inhibited the glycolytic TbGAPDH enzyme in vitro. In light of these results and aware of the antitumor properties of quinones, the anticancer potential of some selected derivatives was investigated. Intriguingly, the tested compounds displayed antitumor activity, while being less toxic against noncancerous cells. The observed cytotoxic potency was ascribed to a multitarget mechanism of action accounting for hGAPDH inhibition and mitochondrial toxicity. Overall, the development of further derivatives, able to finely modulate multiple pathways of cancer or parasite cell metabolism, might lead to more effective treatments against these devastating diseases.
authors.affiliation: Department of Pharmacy & Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6/Via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Prati
authors.affiliation: Department of Pharmacy & Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6/Via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Christian
authors.initials: C
authors.lastname: Bergamini
authors.affiliation: Instituto de Química Médica (IQM-CSIC) , c/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Molina
authors.affiliation: Department of Pharmacy & Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6/Via Irnerio 48, 40126 Bologna, Italy.|Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Falchi
authors.affiliation: Department of Pharmacy & Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6/Via Irnerio 48, 40126 Bologna, Italy.|Department of Drug Discovery and Development, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.affiliation: Swiss Tropical & Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.|University of Basel , Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Swiss Tropical & Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.|University of Basel , Petersplatz 1, 4003 Basel, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.affiliation: Department of Pharmacy & Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6/Via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Romana
authors.initials: R
authors.lastname: Fato
authors.affiliation: Department of Pharmacy & Biotechnology, Alma Mater Studiorum - University of Bologna , Via Belmeloro 6/Via Irnerio 48, 40126 Bologna, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Bolognesi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000037:antagonists & inhibitors; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects; D014349:Trypanosoma cruzi / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D054852:Small Molecule Libraries; D014344:Trypanocidal Agents; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)