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Cite this: Org. Biomol. Chem., 2011, 9, 3080
PERSPECTIVE
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The stimulating adventure of KRN 7000†
Downloaded by Université de Reims Champagne-Ardenne on 01 November 2011 Published on 11 March 2011 on http://pubs.rsc.org | doi:10.1039/C0OB00975J
Aline Banchet-Cadeddu,*a Eric H´enon,a Manuel Dauchez,b Jean-Hugues Renault,a Fanny Monneauxc and Arnaud Haudrechya Received 3rd November 2010, Accepted 12th January 2011 DOI: 10.1039/c0ob00975j Associated with the CD1d protein, KRN 7000, a potent synthetic a-galactosylceramide, is known to activate the invariant NKT immune cells. This stimulation then leads to the production of different cytokines modulating a TH 1/TH 2 immune response balance involved in protection against several pathologies such as autoimmune diseases and cancers. Various efforts have been made toward the synthesis of simple and more functionalized analogues in order to selectively induce TH 1 or TH 2-type cytokine production. Since the discovery of KRN 7000, structure-activity relationships, crystallographic and modelling studies have pointed to the potential of several GalCer analogues in term of selective bioactivity, and have highlighted interesting elements in order to better understand the recognition and activation mechanisms of immune iNKT cells. By presenting an up-to-date library of analogues, collecting recent breakthroughs done in crystallography and molecular modelling, and relating them to the available biological results, we hope that this review will highlight and help the scientific community in their KRN research.
1. Introduction a ICMR-CNRS UMR 6229, Universit´e de Reims Champagne-Ardenne, BP 1039, 51687 REIMS cedex, France. E-mail:
[email protected]; Fax: + 33(0)326913166 (ICMR); Tel: + 33(0)678619782 b MEDyC-CNRS UMR 6237, Universit´e de Reims Champagne-Ardenne, BP 1039, 51687 REIMS cedex, France c IBMC-CNRS UPR 9021, Universit´e de Strasbourg, 67084 STRASBOURG cedex, France † Dedicated to the members of the first GlycoLipid European Network (GLEN http://glen.univ-reims.fr) created the 16th of February, 2009
Aline Banchet-Cadeddu was born in 1981 in France. In 2007, she received her PhD degree from the University of Reims, France, under the supervision of Prof. A. Haudrechy. Her research mainly concerned the development of a new synthetic strategy to prepare C-glycoside skeletons, and the synthesis of an ester analogue of KRN 7000. In 2008, she joined the group of Prof. A. G. M. Barrett as a postdoctoral fellow at Imperial College, London (EngAline Banchet-Cadeddu land) working on medicinal chemistry projects for Cancer Research UK. In 2009–2010, she was a science teacher at the French High School in London.
3080 | Org. Biomol. Chem., 2011, 9, 3080–3104
Nature abounds with an amazing amount of potentially bioactive compounds and has always aroused the interest of scientists. Marine invertebrates are known to be an important reservoir of such molecules.1 At the present time, few drugs are actually derived from marine organisms, but several promising molecules are currently in preclinical/clinical trials.2 Sponges, the simplest and most ancient multicellular animals on Earth, are the principal source of diverse bioactive cerebrosides. The
After receiving his MSc in the group of Prof. Rivail (Nancy University), Eric H´enon obtained his PhD in theoretical chemistry in 1997 from University of Reims ChampagneArdenne. His research was carried out in atmospheric chemistry in the group of Prof. Jacon where he investigated reaction mechanisms using kinetic theories (TST, VTST, RRKM) combined to quantum chemistry to calculate reaction rates. He was Eric H´enon appointed full professor in 2008. Since he joined the Institut de Chimie Mol´eculaire de Reims, his research has been focusing on Organic/Bioorganic chemistry problems.
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