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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.

Author information

1
†Helmholtz-Zentrum Dresden-Rossendorf, Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Bautzner Landstrasse 400, 01328 Dresden, Germany.
2
‡Department of Chemistry and Food Chemistry, Technische Universität Dresden, 01062 Dresden, Germany.
3
§Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada T6G 1Z2.
4
∥Helmholtz-Zentrum Dresden-Rossendorf, Department of Neuroradiopharmaceuticals, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, Permoserstrasse 15, 04318 Leipzig, Germany.
5
○Department of Inorganic Solid State Chemistry, Institute of Chemistry, University of Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany.

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).

PMID:
25909690
DOI:
10.1021/acs.joc.5b00537
[Indexed for MEDLINE]

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