B200
Novel cambinol analogues as sirtuin inhibitors: design, synthesis and biological evaluation
Federico Medda1, Anna R. McCarthy1, Rupert Russell1, Joana Campbell2, Maureen Higgins2, Sonia Lain2, Nicholas J. Westwood1
1Centre for Biomolecular Sciences,University of St Andrews, St Andrews, Fife, UK, 2Departement of Surgery and Molecular Oncology, Medical School, University of Dundee, Dundee, UK
The sirtuin family of deacetylases has become the subject of intensive studies partly due to the role SIRT1 plays in p53 activation and the potential knock-on effects of this for cancer therapy. Bedalov has previously reported the structure of a sirtuin ihibitor, known as cambinol [1]. He also demonstrated that cambinol may be of relevance to the treatment of cancer. Here we present the synthesis and biological evaluation of a series of cambinol and splitomicin derived inhibitors. The splitomicin analogues did not show inhibitory activity against SIRT1 and SIRT2. It was shown that by modifying substituents in cambinol, a significant increase in inhibitory activity and selectivity could be achieved. Ligand docking studies were carried out to rationalise the obtained structure activity relationships (SARs) for our active compounds. The novel cambinol analogues and the parallel synthesis routes we have established may represent a starting point for the development of new selective and potent inhibitors and may act as tools for studying the biochemistry of these enzymes. Links between inhibition of sirtuins with this compound family and cancer treatment are under investigation.
References
[1] Heltweg, Birgit; Gatbonton, Tonibelle; Schuler, Aaron D.; Posakony, Jeff; Li, Hongzhe; Goehle, Sondra; Kollipara, Ramya; DePinho, Ronald A.; Gu, Yansong; Simon, Julian A.; Bedalov, Antonio. Antitumor Activity of a Small-Molecule Inhibitor of Human Silent Information Regulator 2 Enzymes. Cancer Research (2006), 66(8), 4368-4377.
