新型大黄酸酰胺类破骨细胞抑制剂抗乳腺癌骨转移瘤活性评价及机制研究

Bone is one of earliest and the most commonly metastatic organs, thus controlling breast cancer bone metastasis has become an important task in anti-breast cancer treatment. Rhein, as a natural product, have multiple activities while with relative moderate anti-osteoclast activity. In our preliminary studies, we had synthesized a series of rhein derivatives retaining its bone-seeking groups. In this project we are determined to investigate their anti-osteoclast activities and choose a derivative, which is better than rhein, to explore its mechanisms and effects in breast cancer bone metastasis. Base on our previously achieved results, we have determined derivative d6 is the best one using our inhibitor screening platform. We will further focus on the concrete mechanisms of d6 on osteoclast activity and function through its target P2X7 receptor. In addition, we will also test its acute toxicity in mice and evaluate its effects in anti-breast cancer bone metastasis through technologies such as in vivo small animal imaging, micro-CT, histomorphometry and so on. The results in our study will not only provide promising drug in breast cancer bone metastasis treatment, the study of mechanisms of P2X7 receptor in breast cancer bone metastasis, using d6 as a probe, also help to confirm the theoretical basis for targeting P2X7 receptor in treating breast cancer bone metastasis and to obtain promising anti-breast cancer bone metastasis drug lead compounds.

骨骼是乳腺癌最早也是最常见的转移部位之一，控制乳腺癌骨转移已成为乳腺癌治疗的一项重要工作。天然产物大黄酸具有多种活性，包括中等程度的破骨细胞抑制活性。本课题组前期保留其趋骨性基团改造了系列衍生物，本项目拟对该系列化合物进行破骨细胞抑制活性筛选，并选择活性优于大黄酸的衍生物进行深入的机制与药效学研究。项目工作基础中我们通过抑制剂筛选平台发现衍生物d6，接下来我们还将通过细胞与分子生物学研究手段研究d6通过其作用靶点P2X7受体调节破骨细胞活性与功能的具体作用机制，评价d6的动物急性毒性作用，并通过小动物活体成像、micro-CT、组织计量学等多种手段明晰d6抗乳腺癌溶骨性骨转移的药效。本项目不仅为抗乳腺癌骨转移治疗提供潜在的治疗手段，同时以d6为分子探针对P2X7受体在乳腺癌骨转移中药理作用机制的探索，也将有助于确证抗骨转移瘤新靶点并寻找新型抗骨转移瘤治疗的先导化合物。

骨骼是乳腺癌最早也是最常见的转移部位之一，控制乳腺癌骨转移已成为乳腺癌治疗的一项重要工作，控制骨转移与抑制破骨细胞活性有密切关系。天然产物大黄酸具有多种活性，包括中等程度的破骨细胞抑制活性。本课题组基于大黄酸的趋骨性基团，继续改造了系列衍生物，选择活性优于大黄酸和d6的衍生物进行深入的机制与药效学研究。.我们通过抑制剂平台的筛选，发现衍生物1040具有明显的破骨细胞分化抑制活性，并对P2X7受体表现出明显的拮抗活性，1040通过ERK1/2，p38和JNK1/2磷酸化的途径抑制了破骨细胞的分化；遗憾的是，在后续动物体内抗乳腺癌溶骨性骨转移的评价中1040并未表现出明显抗乳腺癌骨转移效果。.同时，我们基于H2S在骨代谢中的重要角色，我们制备了大黄酸磺酰胺化合物RT。通过细胞与分子生物学研究及对防治绝经后骨质疏松症的评价，我们发现RT可抑制破骨细胞活性并在一定程度上延缓绝经后骨质疏松导致的骨丢失。.本项目对大黄酸的深入研究为弘扬传统中药文化做出贡献，为开发具有自主知识产权的防治破骨细胞活跃相关的疾病（如骨质疏松或乳腺癌骨转移）的创新药物研究提供了新的先导化合物。

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