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Open AccessCommunication

Synthesis and Cyclooxygenase Inhibition of Sulfonamide-Substituted (Dihydro)Pyrrolo[3,2,1-hi]indoles and Their Potential Prodrugs

1
Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany
2
Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstrasse 4, 01062 Dresden, Germany
*
Authors to whom correspondence should be addressed.
Academic Editor: David StC Black
Molecules 2019, 24(20), 3807; https://doi.org/10.3390/molecules24203807
Received: 26 September 2019 / Revised: 17 October 2019 / Accepted: 18 October 2019 / Published: 22 October 2019
(This article belongs to the Special Issue Indole Derivatives: Synthesis and Application)
Non-invasive imaging of cyclooxygenase-2 (COX-2) by radiolabeled ligands is attractive for the diagnosis of cancer, and novel highly affine leads with optimized pharmacokinetic profile are of great interest for future developments. Recent findings have shown that methylsulfonyl-substituted (dihydro)pyrrolo[3,2,1-hi]indoles represent highly potent and selective COX-2 inhibitors but possess unsuitable pharmacokinetic properties for radiotracer applications. Based on these results, we herein present the development and evaluation of a second series of sulfonamide-substituted (dihydro)pyrrolo[3,2,1-hi]indoles and their conversion into the respective more hydrophilic N-propionamide-substituted analogs. In comparison to the methylsulfonyl-substituted leads, COX inhibition potency and selectivity was retained in the sulfonamide-substituted compounds; however, the high lipophilicity might hinder their future use. The N-propionamide-substituted analogs showed a significantly decreased lipophilicity and, as expected, lower or no COX-inhibition potency. Hence, the N-(sulfonyl)propionamides can be regarded as potential prodrugs, which represents a potential approach for more sophisticated radiotracer developments. View Full-Text
Keywords: cancer; imaging; inflammation; lipophilicity; McMurry cyclization; structure-activity-relationship cancer; imaging; inflammation; lipophilicity; McMurry cyclization; structure-activity-relationship
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MDPI and ACS Style

Laube, M.; Gassner, C.; Kniess, T.; Pietzsch, J. Synthesis and Cyclooxygenase Inhibition of Sulfonamide-Substituted (Dihydro)Pyrrolo[3,2,1-hi]indoles and Their Potential Prodrugs. Molecules 2019, 24, 3807.

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