Design, synthesis, and biological evaluation of novel 1-amido-2-one-4-thio-deoxypyranose as potential antitumor agents for multiple myeloma

[Display omitted] •A series of novel 1-amido-2-oxo-4-thio-deoxypyranoses were efficiently synthesized for first time from easily available α, β-unsaturated ketone.•The most active compounds C16, C18, C20 and C32 exhibited strong anti-proliferative activity with IC50 values of 1 ∼ 2 μM.•Compound 20 as a potent ligand and inhibitor of TRIP13 exhibited anticancer efficacy both in vitro and in vivo.•All the results suggested that the 1-amido-2-oxo-4-thio-deoxypyranoses are promising lead compounds for developing carbohydrate-based TRIP13 inhibitor drugs, which are in structure totally different from already reported inhibitors. This study reported the design and synthesis of novel 1-amido-2-one-4-thio-deoxypyranose as inhibitors of potential drug target TRIP13 for developing new mechanism-based therapeutic agents in the treatment of multiple myeloma (MM). In comparison with the positive control DCZ0415, the most active compounds C16, C18, C20 and C32 exhibited strong anti-proliferative activity against human MM cell lines (ARP-1 and NCI-H929) with IC50 values of 1 ∼ 2 μM. While the surface plasmon resonance (SPR) and ATPase activity assays demonstrated that the representative compound C20 is a potent inhibitor of TRIP13, C20 also showed good antitumor activity in vivo on BALB/c nude mice xenografted with MM tumor cells. An initial structure–activity study showed that the carbonyl group is crucial for anticancer activity. Overall, this study provided novel 1-amido-2-one-4-thio-deoxypyranoses, which are entirely different from previously reported potent inhibitor structures of TRIP13, and thus would aid the development of carbohydrate-based novel agents in MM pharmacotherapy.