Isonimesulide and Its Carborane Analogues as Isoform-Selective COX Inhibitors and Antitumor Agents
2023
Authors:
Useini, LiridonaKomazec, Teodora
Laube, Markus
Lönnecke, Peter
Schädlich, Jonas
Mijatović, Sanja
Maksimović-Ivanić, Danijela
Pietzsch, Jens
Hey-Hawkins, Evamarie
Document Type:
Article (Published version)
Metadata
Show full item recordAbstract:
Nonsteroidal 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.
Keywords:
cancer; carborane; cyclooxygenase; drug design; inflammations; nimesulide; nonsteroidal anti-inflammatory drugsSource:
Advanced Therapeutics, 2023, 2300117-Funding / projects:
- The Deutscher Akademischer Austauschdienst (DAAD, Research Grants–Doctoral Programs in Germany 2018/2019, Funding Program No. 57381412)
- The Graduate School Leipzig School of Natural Sciences – Building with Molecules and Nanoobjects (BuildMoNa)
- The German Research Foundation (Deutsche Forschungsgemeinschaft)
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
DOI: 10.1002/adtp.202300117
ISSN: 2366-3987