Abstract
We report the synthesis and biological evaluation of a light‐activated (caged) prodrug of the KDAC inhibitor panobinostat (Zap‐Pano). We demonstrate that addition of the 4,5‐dimethoxy‐2‐nitrobenzyl group to the hydroxamic acid oxygen results in an inactive prodrug. In two cancer cell lines we show that photolysis of this compound releases panobinostat and an unexpected carboxamide analogue of panobinostat. Photolysis of Zap‐Pano causes an increase in H3K9Ac and H3K18Ac, consistent with KDAC inhibition, in an oesophageal cancer cell line (OE21). Irradiation of OE21 cells in the presence of Zap‐Pano results in apoptotic cell death. This compound is a useful research tool, allowing spatial and temporal control over release of panobinostat.
Highlights
Protein post-translational modifications (PTMs) add a layer of complexity to the proteome and provide mechanisms to finetune protein function.[1]
Others, have previously demonstrated that substitution on the hydroxamic acid oxygen atom is an effective strategy for developing prodrugs of KDAC inhibitors
We synthesised the carboxamide analogue of Pano, 15, as this compound was detected as a by-product in the photolysis reaction
Summary
Protein post-translational modifications (PTMs) add a layer of complexity to the proteome and provide mechanisms to finetune protein function.[1] Lysine acetylation is a well-established PTM[2] that is found in over 3600 locations on over 1750 proteins throughout the cellular environment.[3,4] Recently, there has been a particular focus on lysine acetylation in histone proteins, which play a key role in the organisation of DNA in chromatin. Acetylation leads to the formation of an amide, which removes the positive charge from the ɛ-nitrogen atom of lysine, resulting in a weaker association with negatively charged DNA, and the formation of euchromatin. This more relaxed form of chromatin is associated with transcriptional activation.
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