四氢异喹啉生物碱Renieramycin T衍生物的合成及其抗肿瘤侵袭转移作用机制研究

在海洋药物研究中，四氢异喹啉生物碱是非常活跃的研究领域，也是寻找和发现抗肿瘤药物先导化合物的重要源泉。Renieramycin T具有较强的抗肿瘤活性，但有关其抑制微环境中肿瘤侵袭转移作用及机制尚未见报道。前期研究发现renieramycin T可抑制人单核巨噬细胞上清液刺激下小鼠黑色素瘤细胞中STAT3蛋白的磷酸化及Nrf2蛋白的表达。IL-6诱导的肿瘤细胞中STAT3/Nrf2通路能促进肿瘤细胞的侵袭转移，提示其有可能通过调控IL-6/STAT3/Nrf2通路抑制肿瘤细胞侵袭转移。本项目拟合成renieramycin T衍生物，从细胞外环境、肿瘤细胞和炎症细胞三者构成的肿瘤微环境网络互动角度，模拟肿瘤侵袭转移的过程，研究其在肿瘤微环境中抑制肿瘤侵袭转移的作用，探索STAT3/Nrf2信号通路对肿瘤侵袭转移的调控作用及机制，进一步阐明肿瘤侵袭转移中的关键分子事件，为肿瘤治疗提供新的思路。

In marine drug research, the study on tetrahydroisoquinoline alkaloids is a very active field, and is also an important source of finding and discovering the leading molecules of natural anti-tumor drugs. The renieramycin T has strong effects of anti-tumor in vitro and in vivo, but the effect of renieramycin T on the invasion and metastasis remains unclear. Previous studies showed that renieramycin T could inhibit the phosphorylation of STAT3 protein and the expression of Nrf2 protein in mouse melanoma cells stimulated by human monocyte macrophage supernatant. Recent study showed that STAT3/Nrf2 pathway induced by IL-6 in tumor cells promotes invasion and metastasis, which is believed that renieramycin T may inhibit the invasion and metastasis of tumor cells via STAT3/Nrf2 pathway. This project aims to synthesize renieramycin T analogs and explore the role and mechanistic basis of renieramycin T and its analogs on cancer progression using gene regulation, combined with a variety of in vivo tumor metastasis model and co-culture system composed of tumor cells, inflammatory cells and extracellular factors. This study will provide substantial theoretical supporting for anti-tumor activity of renieramycin T, and hopefully further reveal the key molecular events of tumor invasion and metastasis, and provide a new method for the treatment of malignant tumor.