title: Design, Synthesis, and Biological Characterization of Novel Mitochondria Targeted Dichloroacetate-Loaded Compounds with Antileukemic Activity.
abstract: The mitochondrial kinase inhibitor dichloroacetate (DCA) has recently received attention in oncology due to its ability to target glycolysis. However, DCA molecule exhibits poor bioavailability and cellular uptake with limited ability to reach its target mitochondria. To overcome these biases, we have synthesized novel DCA-loaded compounds. The selection of the most promising therapeutic molecule was evaluated by combining in vitro assays, to test the antitumoral potential on leukemic cells, and a preliminary characterization of the molecule stability in vivo, in mice. Among the newly synthesized compounds, we have selected the multiple DCA-loaded compound 10, characterized by a tertiary amine scaffold, because it exhibited enhanced (>30-fold) in vitro antitumor activity with respect to DCA and increased in vivo stability. On the basis of these results, we believe that compound 10 should be considered for further preclinical evaluations for the treatment of cancers and/or other diseases characterized by altered metabolic origin.
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA Centre, University of Ferrara , Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.affiliation: Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara , 44121 Ferrara, Italy.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Voltan
authors.affiliation: Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara , 44121 Ferrara, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Melloni
authors.affiliation: Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara , 44121 Ferrara, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Tisato
authors.affiliation: Department of Life Sciences, University of Trieste , 34128 Trieste, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Celeghini
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA Centre, University of Ferrara , Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bianco
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA Centre, University of Ferrara , Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Fantinati
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA Centre, University of Ferrara , Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.affiliation: Department of Chemical and Pharmaceutical Sciences and LTTA Centre, University of Ferrara , Via Fossato di Mortara 17, 44121 Ferrara, Italy.
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.affiliation: Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara , 44121 Ferrara, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Secchiero
authors.affiliation: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Via dell'Istria 65/1, 34137 Trieste, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001682:Biological Availability; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003999:Dichloroacetic Acid / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D004355:Drug Stability; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects*; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D011768:Pyruvate Dehydrogenase Complex; D003999:Dichloroacetic Acid; D054462:p21-Activated Kinases