title: Synthesis and structure-activity relationships of novel poly(ADP-ribose) polymerase-1 inhibitors.
abstract: A series of novel pyrrolocarbazoles was synthesized as potential PARP-1 inhibitors. Pyrrolocarbazole 1 was identified as a potent PARP-1 inhibitor (IC50 = 36 nM) from our internal database. Synthesis of analogs around this template with the aid of modeling studies led to the identification of the truncated imide 14. Compound 14 (IC50 = 40 nM), with deleted B-ring, was found to be an equipotent PARP-1 inhibitor.
authors.affiliation: Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380-4245, USA. mtao@cephalon.com
authors.forename: Ming
authors.initials: M
authors.lastname: Tao
authors.forename: Chung Ho
authors.initials: CH
authors.lastname: Park
authors.forename: Ron
authors.initials: R
authors.lastname: Bihovsky
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Wells
authors.forename: Jean
authors.initials: J
authors.lastname: Husten
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ator
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
mesh_terms: D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013329:Structure-Activity Relationship
chemical_list: D002227:Carbazoles; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1