Structure-activity studies on splitomicin derivatives as sirtuin inhibitors and computational prediction of binding mode.

Abstract	NAD (+)-dependent histone deacetylases (sirtuins) are enzymes that cleave acetyl groups from lysines in histones and other proteins. Potent selective sirtuin inhibitors are interesting tools for the investigation of the biological functions of those enzymes and may be future drugs for the treatment of cancer. Splitomicin was among the first two inhibitors that were discovered for yeast sirtuins but showed rather weak inhibition on human enzymes. We present detailed structure-activity relationships on splitomicin derivatives and their inhibition of recombinant Sirt2. To rationalize our experimental results, ligand docking followed by molecular mechanics Poisson-Boltzmann/surface area (MM-PBSA) calculations were carried out. These analyses suggested a molecular basis for the interaction of the beta-phenylsplitomicins with human Sirt2. Protein-based virtual screening resulted in the identification of a novel Sirt2 inhibitor chemotype. Selected inhibitors showed antiproliferative properties and tubulin hyperacetylation in MCF7 breast cancer cells and are promising candidates for further optimization as potential anticancer drugs.
Authors	Robert C Neugebauer, Urszula Uchiechowska, Rene Meier, Henning Hruby, Vassil Valkov, Eric Verdin, Wolfgang Sippl, Manfred Jung
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 51 Issue 5 Pg. 1203-13 (Mar 13 2008) ISSN: 0022-2623 [Print] United States
PMID	18269226 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antineoplastic Agents Naphthalenes Pyrones Recombinant Proteins Tubulin splitomicin SIRT2 protein, human Sirtuin 2 Sirtuins
Topics	Acetylation Antineoplastic Agents (chemical synthesis, chemistry, pharmacology) Catalytic Domain Cell Line, Tumor Databases, Factual Drug Screening Assays, Antitumor Humans Hydrogen Bonding Models, Molecular Naphthalenes (chemical synthesis, chemistry, pharmacology) Protein Binding Pyrones (chemical synthesis, chemistry, pharmacology) Recombinant Proteins (antagonists & inhibitors, chemistry) Sirtuin 2 Sirtuins (antagonists & inhibitors, chemistry) Stereoisomerism Structure-Activity Relationship Thermodynamics Tubulin (chemistry)

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