Suberoylanilide hydroxamic acid (SAHA, Vorinostat), the first FDA-approved histone deacetylase (HDAC) inhibitor drug, was modified at the C6 position to study the structural requirements for high potency and selectivity. Substituents on the C6 position only modestly influenced inhibitor potency, with poorer activity observed as substituent size increased. Interestingly, C6 substituents also modestly influenced selectivity compared to the parent compound, SAHA. This systematic study documenting the influence of substituents on the SAHA linker region will aid development of anti-cancer drugs targeting HDAC proteins.