Boehmeriasin A as new lead compound for the inhibition of topoisomerases and SIRT2

  • Eur J Med Chem. 2015 Mar 6:92:766-75. doi: 10.1016/j.ejmech.2015.01.038.
Michael S Christodoulou  1 ,  Francesco Calogero  1 ,  Marcus Baumann  2 ,  Aída Nelly García-Argáez  3 ,  Stefano Pieraccini  1 ,  Maurizio Sironi  1 ,  Federico Dapiaggi  1 ,  Raffaella Bucci  1 ,  Gianluigi Broggini  4 ,  Silvia Gazzola  4 ,  Sandra Liekens  5 ,  Alessandra Silvani  1 ,  Maija Lahtela-Kakkonen  6 ,  Nadine Martinet  7 ,  Alfons Nonell-Canals  8 ,  Eduardo Santamaría-Navarro  8 ,  Ian R Baxendale  2 ,  Lisa Dalla Via  3 ,  Daniele Passarella  9
Affiliations
  • 1. Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy.
  • 2. Department of Chemistry, University of Durham, South Road, DH1 3LE, Durham, United Kingdom.
  • 3. Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via F. Marzolo 5, 35131 Padova, Italy.
  • 4. Dipartimento di Scienza e Alta Tecnologia, Università degli Studi dell'Insubria, Via Valleggio 11, 22100 Como, Italy.
  • 5. Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
  • 6. School of Pharmacy, University of Eastern Finland, P. O. Box 1627, 70211 Kuopio, Finland.
  • 7. Institute of Chemistry, UMR CNRS 7272, Parc Valrose, Nice 06108, Cedex 2, France.
  • 8. Mind the Byte, S.L., Parc Científic de Barcelona, C/Baldiri Reixac, 4-8, 08028 Barcelona, Spain.
  • 9. Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy. Electronic address: [email protected].
PMID: 25626146 DOI: 10.1016/j.ejmech.2015.01.038
Abstract

Two synthetic approaches to boehmeriasin A are described. A gram scale racemic preparation is accompanied by an efficient preparation of both the pure enantiomers using the conformationally stable 2-piperidin-2-yl acetaldehyde as starting material. The anti-proliferative activity in three Cancer cell lines (CEM, HeLa and L1210) and two endothelial cell lines (HMEC-1, BAEC) indicates promising activity at the nanomolar range. Topoisomerases and SIRT2 are identified as biological targets and the experimental data has been supported by docking studies.

Keywords
Boehmeriasin A; Sirtuins inhibition; Topoisomerases inhibition; Total synthesis.