Synthesis and Structure–Activity
Relationship
of 3‑Hydroxypyridine-2-thione-Based Histone Deacetylase Inhibitors
- Publication date
- Publisher
Abstract
We
previously identified 3-hydroxypyridine-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 devoid of HDAC1 inhibition. To delineate further
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, <b>10d</b> and <b>14e</b>, with potent HDAC6 and HDAC8 activities that
are inactive against HDAC1. These new HDACi possess anticancer activities
against various cancer cell lines including Jurkat J.γ1 for
which SAHA and the previously disclosed 3HPT-derived HDACi were inactive