Isonimesulide and Its Carborane Analogues as Isoform‐Selective COX Inhibitors and Antitumor Agents

Author:

Useini Liridona1ORCID,Komazec Teodora2ORCID,Laube Markus3ORCID,Lönnecke Peter1ORCID,Schädlich Jonas3ORCID,Mijatović Sanja2ORCID,Maksimović‐Ivanić Danijela2ORCID,Pietzsch Jens34ORCID,Hey‐Hawkins Evamarie1ORCID

Affiliation:

1. Faculty of Chemistry and Mineralogy Institute of Inorganic Chemistry Leipzig University 04103 Leipzig Germany

2. Department of Immunology Institute for Biological Research “Siniša Stanković” National Institute of the Republic of Serbia University of Belgrade 11060 Belgrade Serbia

3. Department of Radiopharmaceutical and Chemical Biology Institute of Radiopharmaceutical Cancer Research Helmholtz‐Zentrum Dresden Rossendorf (HZDR) 01328 Dresden Germany

4. Faculty of Chemistry and Food Chemistry School of Science Technical University Dresden 01069 Dresden Germany

Abstract

AbstractNonsteroidal anti‐inflammatory drugs (NSAIDs) are the most widely used therapeutics against pain, fever, and inflammation; additionally, antitumor properties are reported. NSAIDs reduce the synthesis of prostaglandins by inhibiting the cyclooxygenase (COX) isoforms COX‐1 and COX‐2. As nonselective inhibition is associated with off‐target effects, strategies to achieve selectivity for the clinically preferred isoform COX‐2 are of high interest. The modification of NSAIDs using carborane clusters as phenyl mimetics is reported to alter the selectivity profile through size exclusion. Inspired by these findings, isonimesulide and its carborane derivatives are prepared. The biological screening shows that the carborane containing compounds exhibit a stronger antitumor potential compared to nimesulide and isonimesulide. Furthermore, the replacement of the phenyl ring of isonimesulide with a carborane moiety resulted in a shift of the COX activity from nonactive to COX‐active compounds.

Funder

Bundesministerium für Bildung und Forschung

Deutsche Forschungsgemeinschaft

Graduate School BuildMoNa

Deutscher Akademischer Austauschdienst

Publisher

Wiley

Subject

Pharmacology (medical),Biochemistry (medical),Genetics (clinical),Pharmaceutical Science,Pharmacology,Medicine (miscellaneous)

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