Santacruzamate A, a Potent and Selective Histone Deacetylase Inhibitor from the Panamanian Marine Cyanobacterium cf. <i>Symploca</i> sp.

A dark brown tuft-forming cyanobacterium, morphologically resembling the genus <i>Symploca</i>, was collected during an expedition to the Coiba National Park, a UNESCO World Heritage Site on the Pacific coast of Panama. Phylogenetic analysis of its 16S rRNA gene sequence indicated that it is 4.5% divergent from the type strain for <i>Symploca</i> and thus is likely a new genus. Fractionation of the crude extract led to the isolation of a new cytotoxin, designated santacruzamate A (<b>1</b>), which has several structural features in common with suberoylanilide hydroxamic acid [(<b>2</b>), SAHA, trade name Vorinostat], a clinically approved histone deacetylase (HDAC) inhibitor used to treat refractory cutaneous T-cell lymphoma. Recognition of the structural similarly of <b>1</b> and SAHA led to the characterization of santacruzamate A as a picomolar level selective inhibitor of HDAC2, a Class I HDAC, with relatively little inhibition of HDAC4 or HDAC6, both Class II HDACs. As a result, chemical syntheses of santacruzamate A as well as a structurally intriguing hybrid molecule, which blends aspects of both agents (<b>1</b> and <b>2</b>), were achieved and evaluated for their HDAC activity and specificity