Publikationsrepositorium - Helmholtz-Zentrum Dresden-Rossendorf
1 PublikationDiaryl-substituted (dihydro)pyrrolo[3,2,1-hi]indoles, a class of potent COX-2 inhibitors with tricyclic core structure
Laube, M.; Gassner, C.; Sharma, S. K.; Günther, R.; Pigorsch, A.; König, J.; Köckerling, M.; Wuest, F.; Pietzsch, J.; Kniess, T.
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 towards dihydropyrrolo[3,2,1-hi]indoles and is characterized by good chemical yields and high modularity. From a set of nineteen derivatives, eleven candidates were selected for determination of their COX inhibition potency and were found to be highly affine and selective inhibitors with IC50 to COX-2 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 got a fluoro-substituent making them to promising candidates for the development of 18F-radiolabeled COX-2 inhibitors for imaging purposes with positron emission tomography (PET).
Keywords: pyrrolo[3; 2; 1-hi]indoles; selective COX-2 inhibitors; McMurry cyclization; GOLD; docking studies; radiotracer
Beteiligte Forschungsanlagen
- PET-Zentrum
-
Journal of Organic Chemistry 80(2015), 5611-5624
DOI: 10.1021/acs.joc.5b00537
Cited 22 times in Scopus
Permalink: https://www.hzdr.de/publications/Publ-21121