RE12 derivatives displaying Vaccinia H1-related phosphatase (VHR) inhibition in the presence of detergent and their anti-proliferative activity against HeLa cells

Abstract New derivatives of Vaccinia H1-related phosphatase (VHR) inhibitor RE12 ( 5 ) were designed by replacing the long straight alkyl chain with other hydrophobic functionalities containing two aromatic rings, with the aim of obtaining potent, cell-active inhibitors. We established a direct coupling reaction between tetronic acid derivative and thioimidate to prepare the RE derivatives 6a – 6i efficiently. These compounds all showed VHR-inhibitory activity in the presence of 0.001% NP-40, whereas RE12 ( 5 ) was inactive under this condition, even at 100 μM. Further structure–activity studies focused on terminal substitution afforded trifluoromethyl derivative 6k (RE176) and nitro derivative 6l (RE177). The IC 50 value of 6l in the presence of NP-40 was almost equivalent to that of RE12 ( 5 ) in its absence. Compound 6k (RE176) potently inhibited proliferation of HeLa cells.