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Sila-Ibuprofen.

Abstract
The synthesis, characterization, biological activity, and toxicology of sila-ibuprofen, a silicon derivative of the most common nonsteroidal anti-inflammatory drug, is reported. The key improvements compared with ibuprofen are a four times higher solubility in physiological media and a lower melting enthalpy, which are attributed to the carbon-silicon switch. The improved solubility is of interest for postsurgical intravenous administration. A potential for pain relief is rationalized via inhibition experiments of cyclooxygenases I and II (COX-I and COX-II) as well as via a set of newly developed methods that combine molecular dynamics, quantum chemistry, and quantum crystallography. The binding affinity of sila-ibuprofen to COX-I and COX-II is quantified in terms of London dispersion and electrostatic interactions in the active receptor site. This study not only shows the potential of sila-ibuprofen for medicinal application but also improves our understanding of the mechanism of action of the inhibition process.
AuthorsFlorian Kleemiss, Aileen Justies, Daniel Duvinage, Patrick Watermann, Eric Ehrke, Kunihisa Sugimoto, Malte Fugel, Lorraine A Malaspina, Anneke Dittmer, Torsten Kleemiss, Pim Puylaert, Nelly R King, Anne Staubitz, Thomas M Tzschentke, Ralf Dringen, Simon Grabowsky, Jens Beckmann
JournalJournal of medicinal chemistry (J Med Chem) Vol. 63 Issue 21 Pg. 12614-12622 (11 12 2020) ISSN: 1520-4804 [Electronic] United States
PMID32931274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Anti-Inflammatory Agents, Non-Steroidal
  • Carbon
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Ibuprofen
  • Silicon
Topics
  • Anti-Inflammatory Agents, Non-Steroidal (chemical synthesis, chemistry, metabolism)
  • Binding Sites
  • Carbon (chemistry)
  • Catalytic Domain
  • Cyclooxygenase 1 (chemistry, metabolism)
  • Cyclooxygenase 2 (chemistry, metabolism)
  • Humans
  • Ibuprofen (chemistry, metabolism)
  • Molecular Conformation
  • Molecular Dynamics Simulation
  • Protein Binding
  • Quantum Theory
  • Silicon (chemistry)
  • Static Electricity

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