| Summary: | The discovery of IDO1 and HDAC1 dual inhibitors may provide a novel strategy for cancer treatment by taking advantages of both immunotherapeutic and epigenetic drugs. In this paper, saprorthoquinone (<b>1</b>) and 13 of its analogues from <i>Salvia prionitis</i> Hance were investigated for their SAR against IDO1, the results demonstrated the <i>ortho</i>-quinone was a key pharmacophore. Then a series of IDO1 and HDAC dual inhibitors connected by appropriate linkers were designed, synthesized, and evaluated from the hit compound saprorthoquinone (<b>1</b>). Among them, compound <b>33d</b> showed balanced activity against both IDO1 (IC<sub>50</sub> = 0.73 μM) and HDAC1 (IC<sub>50</sub> = 0.46 μM). Importantly, the structure of <b>33d</b> suggested that an <i>ortho</i>-quinone pharmacophore and a <i>N</i>-(2-aminophenyl) amide pharmacophore were necessary for the IDO inhibition and HDAC inhibition respectively. Meanwhile, these two pharmacophore groups should be combined by a pentane linker. Moreover, the binding modes of <b>33d</b> to the enzyme active site showed that the hydrogen bond with Leu234 of IDO1 appeared to confer increased potency to this class of inhibitors, which may explain the higher activity of <b>33d</b>. This study provides a new strategy for future IDO1/HDAC dual inhibitors with synergistic antitumor activity started from lead compound <b>33d</b>.
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