title: Diaryl-Substituted (Dihydro)pyrrolo[3,2,1-hi]indoles, a Class of Potent COX-2 Inhibitors with Tricyclic Core Structure.
abstract: A new compound class of diaryl-substituted heterocycles with tricyclic dihydropyrrolo[3,2,1-hi]indole and pyrrolo[3,2,1-hi]indole core structures has been designed and was synthesized by a modular sequence of Friedel-Crafts acylation, amide formation, and McMurry cyclization. This synthesis route represents a novel and versatile access toward dihydropyrrolo[3,2,1-hi]indoles and is characterized by good chemical yields and high modularity. From a set of 19 derivatives, 11 candidates were selected for determination of their COX inhibition potency and were found to be selective inhibitors with high affinity to COX-2 (IC50 ranging from 20-2500 nM and negligible inhibition of COX-1). The binding mode of the novel inhibitors in the active side of COX-2 was calculated in silico using the protein-ligand docking program GOLD by application of the molecular structures of two compounds derived from X-ray crystallography. Two novel compounds with high affinity to COX-2 (6k = 70 nM, 8e = 60 nM) have a fluoro substituent, making them promising candidates for the development of (18)F-radiolabeled COX-2 inhibitors for imaging purposes with positron emission tomography (PET).
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328 Dresden, Germany.|‡Department of Chemistry and Food Chemistry, Technische Universität Dresden, 01062 Dresden, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Laube
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328 Dresden, Germany.|‡Department of Chemistry and Food Chemistry, Technische Universität Dresden, 01062 Dresden, Germany.
authors.forename: Cemena
authors.initials: C
authors.lastname: Gassner
authors.affiliation: §Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada T6G 1Z2.
authors.forename: Sai Kiran
authors.initials: SK
authors.lastname: Sharma
authors.affiliation: ∥Helmholtz-Zentrum Dresden-Rossendorf, Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Permoserstrasse 15, 04318 Leipzig, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Günther
authors.affiliation: ○Department of Inorganic Solid State Chemistry, Institute of Chemistry, University of Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany.
authors.forename: Arne
authors.initials: A
authors.lastname: Pigorsch
authors.affiliation: ○Department of Inorganic Solid State Chemistry, Institute of Chemistry, University of Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: König
authors.affiliation: ○Department of Inorganic Solid State Chemistry, Institute of Chemistry, University of Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Köckerling
authors.affiliation: §Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada T6G 1Z2.
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328 Dresden, Germany.|‡Department of Chemistry and Food Chemistry, Technische Universität Dresden, 01062 Dresden, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.affiliation: †Helmholtz-Zentrum Dresden-Rossendorf, Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328 Dresden, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Kniess
mesh_terms: D000215:Acylation; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry*; D015195:Drug Design; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D011758:Pyrroles / Q000737:chemistry*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D007211:Indoles; D011758:Pyrroles; C000605294:dihydropyrrolo(3,2,1-hi)indole