Synthesis and Structure Activity Relationship of 3-Hydroxypyridin-2-thione Based Histone Deacetylase Inhibitors

• Published in: Journal of medicinal chemistry 2013-12, Vol.56 (24), p.9969-9981
• Main Authors: Sodji, Quaovi H., Patil, Vishal, Kornacki, James R., Mrksich, Milan, Oyelere, Adegboyega K.
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401225q

We have previously identified 3-hydroxypyridin-2-thione (3HPT) as a novel zinc binding group for histone deacetylase (HDAC) inhibition. Early structure activity relationship (SAR) studies led to various small molecules possessing selective inhibitory activity against HDAC6 or HDAC8 but are devoid of HDAC1 inhibition. To further delineate the depth of the SAR of 3HPT-derived HDAC inhibitors (HDACi), we have extended the SAR studies to include the linker region and the surface recognition group to optimize the HDAC inhibition. The current efforts resulted in the identification of two lead compounds 10d and 14e with potent HDAC6 and HDAC8 activities, but that are inactive against HDAC1. These new HDACi possess anti-cancer activities against various cancer cell lines including Jurkat J-γ1 against which SAHA and the previously disclosed 3HPT-derived HDACi were inactive.