Discovery and development of Santacruzamate A, a potent and selective histone deacetylase inhibitor

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), a clinically approved histone deacetylase (HDAC) inhibitor used to treat refractory cutaneous T-cell lymphoma (trade name Vorinostat®). As a result of this recognition of the structural similarly of santacruzamate and Vorinostat, this project was pursued by chemical synthesis of santacruzamate A as well as structurally intriguing hybrid structures blending aspects of both agents. 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. With a robust synthesis in place, additional analogs of santacruzamate A have been synthesized and a broader biological evaluation has been conducted.