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

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.

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。

四氢异喹啉生物碱以其独特的结构、优越的生物活性，颇受化学家和药学家的关注。Renieramycin T是一类极具代表性的天然产物，在相关新药研发上具有较好的潜力。本项目主要是以renieramycin T为合成目标，优化了合成路线，发展出基于高选择性的 Pictet-Spengler 环化偶联反应的合成路线，并合成了一系列衍生物。在这些研究基础上，经探索取得如下结果：（1）优化了合成路线，有效地合成了renieramycin T及其衍生物。（2）通过体外构建条件培养细胞模型和体内构建炎症细胞诱导肿瘤侵袭转移的动物模型，模拟肿瘤侵袭转移的过程，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的角度，结果表明renieramycin T能够抑制微环境中肿瘤侵袭转移作用。（3）我们通过构建体外模型进行机制研究，结果显示renieramycin T能够通过调控IL6-STAT3-Nrf2这一信号通路抗肿瘤侵袭转移，为renieramycin T的抗肿瘤治疗提供新的研究靶点。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。