Planta Med 2012; 78 - PD25
DOI: 10.1055/s-0032-1320383

Structure-activity investigations of Santacruzamate A, a potent histone deacetylase inhibitor isolated from a Panamanian cyanobacterium

CM Pavlik 1, MJ Balunas 1
  • 1Division of Medicinal Chemistry, Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269, USA

Recently a new natural product, santacruzamate A, has been isolated from a dark brown cyanobacterium closely related to the genus Symploca. Santacruzamate A contains a unique scaffold analogous to several other potent histone deacetylase (HDAC) inhibitors. Initial in vitro HDAC2 enzyme inhibition bioassay data has shown that the natural product is selective for class I HDAC proteins with an IC50 in the picomolar range. Comparative analysis with the clinically approved HDAC inhibitor, Vorinostat®, demonstrated that the isolated natural product was found to be approximately 1000-fold more potent. Similar to Vorinostat and many other known HDAC inhibitors, santacruzamate A contains three specific regions: a zinc-binding group (ZBG), an alkyl-linker, and a hydrophobic-cap group. Our initial SAR investigation involved modification of our presumed ZBG terminus and subsequent evaluation for class I and II HDAC enzyme inhibition and cell cytoxicity.