Efficient synthesis and biological activity of Psammaplin A and its analogues as antitumor agents

We describe a new concise method for the synthesis of psammaplin A and its analogues, and antitumor activity of psammaplin A analogues. Psammaplin A was obtained with 41% yield in 5 steps from 3-bromo-4-hydroxybenzaldahyde and ethyl acetoacetate via Knoevenagel condensation and α-nitrosation as key steps. Twenty eight analogues of psammaplin A were prepared employing the new synthetic approach. Structure–activity relationship study against cytotoxicity reveal that the free oxime group and disulfide functional group were responsible for high cytotoxicity. Also the bromotyrosine component was relatively tolerable and hydrophobic aromatic groups preserved the cytotoxicity. The cytotoxicity of aromatic group is dependent on the size and spatial geometry. Among them, five compounds showed comparable cytotoxicity to psammaplin A. Compound 30 exhibited potential HDAC inhibitory activity and in vivo antitumor activity. A new and concise synthetic method of psammaplin A was developed by direct α-nitrosation as a key step and structure–activity relationship study along with in vivo study against antitumor activity were performed. [Display omitted] •A new and concise synthetic method of psammaplin A via α-nitrosation was developed.•Structure–activity relationship study against cytotoxicity was performed.•The free oxime and disulfide functional groups were responsible for high cytotoxicity.•The mechanism of cytotoxicity relies on the inhibition of HDAC.•The most potent β-naphthyl analogue (30) inhibited in vivo tumor growth in xenograft models.