Camptothecin-psammaplin A hybrids as topoisomerase I and HDAC dual-action inhibitors

  • Eur J Med Chem. 2018 Jan 1:143:2005-2014. doi: 10.1016/j.ejmech.2017.11.021.
Raffaella Cincinelli  1 ,  Loana Musso  1 ,  Roberto Artali  2 ,  Mario Guglielmi  3 ,  Erminia Bianchino  3 ,  Francesco Cardile  3 ,  Fabiana Colelli  3 ,  Claudio Pisano  3 ,  Sabrina Dallavalle  4
Affiliations
  • 1. Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università degli Studi di Milano, via Celoria 2, 20133 Milan, Italy.
  • 2. Scientia Advice, di Roberto Artali, 20832 Desio, MB, Italy.
  • 3. Biogem, Research Institute, Ariano Irpino, AV, Italy.
  • 4. Department of Food, Environmental and Nutritional Sciences, Division of Chemistry and Molecular Biology, Università degli Studi di Milano, via Celoria 2, 20133 Milan, Italy. Electronic address: [email protected].
PMID: 29150335 DOI: 10.1016/j.ejmech.2017.11.021
Abstract

Recent studies have demonstrated enhanced Anticancer effects of combination therapy consisting of camptothecin derivatives and HDAC inhibitors. To exploit this synergy in a single active compound, we designed new dual-acting multivalent molecules simultaneously targeting Topoisomerase I and HDAC. In particular, a selected compound containing a camptothecin and the psammaplin A scaffold showed a broad spectrum of antiproliferative activity, with IC50 values in the nanomolar range. Preliminary in vivo results indicated a strong antitumor activity on human mesothelioma primary cell line MM473 orthotopically xenografted in CD-1 nude mice and very high tolerability.

Keywords
Antiproliferative activity; Antitumor activity; Camptothecin; Dual-action inhibitors; HDAC inhibitors; Psammaplin.