Thursday, August 16, 2012: 3:30 PM
Meeting Room 6, Columbia Hall, Terrace level (Washington Hilton)
During an expedition to the Coiba National Park, a UNESCO World Heritage Site on the Pacific coast of Panama, in a unique reef habitat near Santa Cruz Island, a dark brown cyanobacterium was collected that morphologically resembled the Symploca genus of marine cyanobacteria. Further 16S rRNA analysis was used to determine the phylogenetic relationship with known cyanobacteria and preliminary results indicate that the genetic variation may be sufficient to propose this as a new genus. In addition, bioactivity-guided fractionation led to the isolation of the new compound, santacruzamate A, which has several structural features in common with SAHA (suberoylanilide hydroxamic acid; trade name Vorinostat®), a clinically approved histone deacetylase (HDAC) inhibitor used to treat refractory cutaneous T-cell lymphoma. As a result of the structural similarly of santacruzamate A and Vorinostat, the natural product and several structurally intriguing hybrid structures were tested for HDAC activity. Santacruzamate A was found to selectively inhibit Class I HDAC activity with picomolar level inhibition of HDAC2 and relatively little inhibition of HDAC4, a Class II HDAC enzyme. 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. With a robust synthesis in place, additional analogs of santacruzamate A have been synthesized and a broader biological evaluation has been conducted.