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J Org Chem. 2015 Jun 5;80(11):5611-24. doi: 10.1021/acs.joc.5b00537. Epub 2015 May 13.

Diaryl-Substituted (Dihydro)pyrrolo[3,2,1-hi]indoles, a Class of Potent COX-2 Inhibitors with Tricyclic Core Structure.

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†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.
§Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada T6G 1Z2.
∥Helmholtz-Zentrum Dresden-Rossendorf, Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Permoserstrasse 15, 04318 Leipzig, Germany.
○Department of Inorganic Solid State Chemistry, Institute of Chemistry, University of Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany.


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).

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