Design, synthesis, and biological evaluation of naphthoylamide derivatives as inhibitors of STAT3 phosphorylation

The phosphorylation of STAT3 plays a critical physiological role in the proliferation of rectal cancer. Hence, inhibiting STAT3 phosphorylation is an effective anticancer approach. In this work, we designed a novel 5-R'-1-naphthylmethylamide scaffold as a small molecule inhibitor of STAT3 phosphorylation. The results showed that 3D and 4D have exceptional inhibitory ability against three different colorectal cancer (CRC) cell lines, and can induce apoptosis of CRC cells by inhibiting STAT3 phosphorylation, while having no killing effect on normal human cells. 3D and 4D can inhibit STAT3 phosphorylation in a time- and concentration-dependent manner, and also inhibit the nuclear translocation of interleukin (IL)-6-induced STAT3. In the in vivo tumor model research, 4D significantly reduced the tumor volume of mice and had no drug toxicity on other organ tissues. Furthermore, molecular docking studies revealed that 3D and 4D had greater binding free energy when interacting with the STAT3 SH2 structural domain, and could establish H-pi interaction modes. Dynamic simulation studies indicated that both compounds were able to bind tightly to STAT3. Based on the structures of nine existing STAT3 phosphorylation inhibitors, a novel small-molecule compound with a simple structure was constructed. Derivative 4D exhibited good biological activity in colorectal cancer cell lines, induced apoptosis of tumor cells, and showed good bioactivity in vitro and in vivo, exerting its biological activity by inhibiting STAT3 phosphorylation. 4D also significantly reduced the tumor tissue in mouse tumor models. image