2 research outputs found
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