Rosser, Callum

University of Sydney (Australia)

Callum Rosser is a young principal investigator within the Chemical Biology and Drug Discovery group from the University of Sydney


The synthesis and activity of analogues of the HDAC inhibitor panobinostat with added hydrogen bonding capacity.


Histone deacetylase (HDAC) enzymes are crucial structural modulators of chromatin, which affect differentiation, cell proliferation and homeostasis of eukaryotic cells [1]. Overexpression of HDACs plays a role in cancer, neurological diseases, infection, and inflammation [1]. Currently, HDAC inhibitors have been approved for use in non-solid cancers, with benefit coupled with serious adverse effects. The low specificity of inhibitors to the HDAC isoforms and other Zn(II) containing metalloproteinases is proposed to cause these adverse effects [2]. This has prompted a search for optimised inhibitors to reduce these side effects. Molecular modelling studies have identified acidic amino acid residues at the surface of HDAC2 capable of forming hydrogen bonds to the cap group region of an HDAC inhibitor [3]. This project aimed to develop a library of cinnamylhydroxamate compounds that incorporate a hydrogen bonding group (carboxamide) to probe these acidic amino acid residues. The naturally occurring amino acid tryptophan, allowed easy addition of the carboxamide group into two regions of the inhibitor using two different synthetic routes. The carboxamide group was incorporated in alternative stereochemical configurations, via the use of L- or D-tryptophan, to explore enantioselective effects. Four cinnamyl-hydroxamate HDAC inhibitors were synthesised and screened for HDAC inhibitory activity in HeLa nuclear extract. Compounds with the carboxamide group in the linker region (5 (225 nM, S), 6 (240 nM, R)) were less potent than approved HDAC inhibitor panobinostat. Compounds with the carboxamide on the cap group (7 (264 nM, S), 8 (1564 nM, R)) possessed similar inhibitory activity to compounds 5 and 6 in the S configuration but reduced inhibitory activity in the R configuration. This project has provided a rationale for the design of new HDAC inhibitors that probe interactions with the acidic amino acid residues at the surface of the HDAC binding pocket.

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