The development of α, β-unsaturated lactam-based andrographolide derivatives as anti-gastric cancer agents with the ability of inhibiting the ERK/c-Fos/Jun pathway.

Gastric cancer remains one of the global health threats for human beings. However, the therapeutic efficacy of the widely-used chemotherapy is usually limited due to the lack of specificity and the related toxicity. Only limited therapeutic agents were demonstrated to show selective and potent inhibitory activity to gastric cancer cells. In this study, we report the first α, β-unsaturated lactam-based andrographolide derivative P16 with the ability to potently and selectively inhibit the proliferation and migration of gastric cancer cells MGC-803. Moreover, the in vivo studies showed that P16 exhibited remarking anti-gastric cancer activity by significantly reducing the growth of tumor without losing the body weight. Further anticancer mechanistic studies indicated that P16 exerted its potent and selective anti-gastric cancer effect by arresting cell cycle at G2/M phase and inducing cancer cell apoptosis through intrinsic mitochondria-mediated pathway. Notably, for the first time, we found that andrographolide derivative P16 could reduce the activities of the ERK/c-Fos/Jun pathway to exert the anti-gastric cancer efficiency. This is the first time to reveal the novel role of ERK/c-Fos/Jun signaling in andrographolide derivative-mediated anti-gastric cancer processes. Overall, derivative P16 represents a valuable candidate for new therapeutic agent discovery in gastric cancer chemotherapy. In addition, pharmacological characterizations of derivative P16, together with another 33 new semi-synthesized andrographolide derivatives, provides a systematic structure-activity relationship (SAR) analysis for this class of compounds, elucidating useful information on structural requirements for potent and selective anti-gastric cancer inhibition.