Discovery of salermide-related sirtuin inhibitors: binding mode studies and antiproliferative effects in cancer cells including cancer stem cells

J Med Chem. 2012 Dec 27;55(24):10937-47. doi: 10.1021/jm3011614. Epub 2012 Dec 12.


Chemical changes performed on 1a (sirtinol) led to a series of SIRT1/2 inhibitors, in some cases more potent than 1a mainly against SIRT1. Tested in human leukemia U937 cells, the benzamide and anilide derivatives 1b, 1c, 2b, and 2c as well as the 4-(2-phenylpropyl)thioanalogue 4c showed huge apoptosis induction, while some sulfinyl and sulfonyl derivatives (5b, 5c, and 6a-c) were highly efficient in granulocytic differentiation. When assayed in human leukemia MOLT4 as well as in human breast MDA-MB-231 and colon RKO cancer cell lines, the anilide 2b (salermide) and the phenylpropylthio analogue 4b emerged as the most potent antiproliferative agents. Tested on colorectal carcinoma and glioblastoma multiforme cancer stem cells (CSCs) from patients, 2b was particularly potent against colorectal carcinoma CSCs, while 4b, 6a, and the SIRT2-selective inhibitor AGK-2 showed the highest effect against glioblastoma multiforme CSCs. Such compounds will be further explored for their broad-spectrum anticancer properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Screening Assays, Antitumor
  • Granulocytes / cytology
  • Granulocytes / drug effects
  • Humans
  • Molecular Docking Simulation
  • Naphthols / chemical synthesis*
  • Naphthols / chemistry
  • Naphthols / pharmacology
  • Neoplastic Stem Cells / cytology
  • Neoplastic Stem Cells / drug effects*
  • Phenylpropionates / chemical synthesis*
  • Phenylpropionates / chemistry
  • Phenylpropionates / pharmacology
  • Protein Binding
  • Sirtuin 1 / antagonists & inhibitors*
  • Sirtuin 2 / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • N-(3-((2-hydroxynaphthalen-1-ylmethylene)amino)phenyl)-2-phenylpropionamide
  • Naphthols
  • Phenylpropionates
  • Sirtuin 1
  • Sirtuin 2