Histone deacetylase inhibitors (HDACi) represent a novel therapeutic option for cancer treatment.  Most HDACi fit into a pharmacophoric model which consists of a surface recognition group that interacts with the outer rim of the HDAC channel, a linker that traverses the hydrophobic channel and most importantly a zinc binding group (ZBG) that chelates a zinc ion located at the active site. In 2006, SAHA (Vorinostat) was approved by the Food and Drug Administration (FDA) for the treatment of cutaneous T-cell lymphoma (CTCL). This prototypical HDACi possesses a hydroxamate as a ZBG which has led to potent HDAC inhibition. However, it inhibits all zinc dependent HDAC isoforms leading to severe side effects. Therefore, isoform selective HDACi will have fewer side effects as these agents will be selective towards particular malignancies which have been shown to overexpress specific HDAC isoforms. Using molecular modeling, we modified the pharmacophoric model resulting in 3-hydroxy-pyridine-2-thione as a novel ZBG for HDAC inhibition. A structure activity relationship (SAR) performed on the linker region and the surface recognition group yielded HDAC 6 or HDAC 8 selective inhibitors. HDAC 8 selective compounds may be affective against T-cell derived malignancies which overexpress HDAC 8 while the HDAC 6 selective compounds may be useful for treatment of neurodegenerative diseases such as Alzheimer's and Huntington's diseases which are linked to HDAC 6 activity. The synthesis of these selective HDACi, and their activities against different human cancer cell lines will be discussed.

Selective histone deacetylase inhibition by 3-hydroxy-pyridin-2-thione based zinc binding group

243rd National Meeting (2012)

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