Design, Synthesis and Bioactivity Evaluation of 4,6-Disubstituted Pyrido[3,2-]pyrimidine Derivatives as Mnk and HDAC Inhibitors.

Both HDACs and Mnks play important role in translating multiple oncogenic signaling pathways during oncogenesis. As HDAC and Mnk are highly expressed in a variety of tumors; thus simultaneous inhibit HDAC and Mnk can increase the inhibition of tumor cell proliferation and provide a new way of inhibiting tumor growth. Based on the previous work and the merge pharmacophore method; we designed and synthesized a series of 4,6-disubstituted pyrido[3,2-]pyrimidine derivatives as HDAC and Mnk dual inhibitors. Among them; compound displayed good HDAC and Mnk inhibitory activity. In vitro antiproliferative assay; compound exhibited the best antiproliferative activity against human prostate cancer PC-3 cells. Docking study revealed that the pyrido[3,2-]pyrimidine framework and hydroxamic acid motif of compound were essential for maintaining the activity of HDAC and Mnk. These result indicated that was a potent Mnk /HDAC inhibitor and will be further researched.