Discovery of Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) and Histone Deacetylase 1 (HDAC1) Dual Inhibitors Derived from the Natural Product Saprorthoquinone.

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 (1) and 13 of its analogues from Salvia prionitis Hance were investigated for their SAR against IDO1, the results demonstrated the ortho-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 (1). Among them, compound 33d showed balanced activity against both IDO1 (IC(50) = 0.73 μM) and HDAC1 (IC(50) = 0.46 μM). Importantly, the structure of 33d suggested that an ortho-quinone pharmacophore and a N-(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 33d 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 33d. This study provides a new strategy for future IDO1/HDAC dual inhibitors with synergistic antitumor activity started from lead compound 33d.