title: On the way to selective PARP-2 inhibitors. Design, synthesis, and preliminary evaluation of a series of isoquinolinone derivatives.
abstract: PARP-1 and PARP-2 are members of the family of poly(ADP-ribose)polymerases, which are involved in the maintenance of genomic integrity under conditions of genotoxic stimuli. The different roles of the two isoforms under pathophysiological conditions have not yet been fully clarified, and this is partially due to the lack of selective inhibitors. We report herein the synthesis and preliminary pharmacological evaluation of a large series of isoquinolinone derivatives as PARP-1/PARP-2 inhibitors. Among them, we identified the 5-benzoyloxyisoquinolin-1(2 H)-one derivative as the most selective PARP-2 inhibitor reported so far, with a PARP-2/PARP-1 selectivity index greater than 60.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, Via del Liceo 1, 06123 Perugia, Italy. rp@unipg.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
authors.forename: Emidio
authors.initials: E
authors.lastname: Camaioni
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
authors.forename: Laura
authors.initials: L
authors.lastname: Formentini
authors.forename: Paola
authors.initials: P
authors.lastname: Sabbatini
authors.forename: Francesco
authors.initials: F
authors.lastname: Venturoni
authors.forename: Gökçen
authors.initials: G
authors.lastname: Eren
authors.forename: Daniele
authors.initials: D
authors.lastname: Bellocchi
authors.forename: Alberto
authors.initials: A
authors.lastname: Chiarugi
authors.forename: Flavio
authors.initials: F
authors.lastname: Moroni
mesh_terms: D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011994:Recombinant Proteins; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C459820:Parp2 protein, mouse