基于溶酶体为靶点的天然产物衍生物制备及抗肿瘤活性研究

与正常细胞相比，肿瘤细胞中溶酶体数量更多、体积更大、膜稳定性更差，加之溶酶体介导的细胞死亡途径是抗肿瘤和逆转肿瘤耐药的重要机制，这为我们设计特异性靶向溶酶体的药物提供了依据。本课题在前期发现的三类靶向溶酶体天然化合物的基础上，利用溶酶体是酸性细胞器的特点，提出基于溶酶体为靶点的天然产物衍生物制备及抗肿瘤活性研究，通过对具有抗肿瘤活性的三类化合物进行结构修饰，引入相应的碱性基团，兼顾溶酶体靶向和溶酶体膜亲和性，构建不同Pka值的弱碱性化合物；在体外筛选抗肿瘤活性的基础上，研究不同结构的化合物在溶酶体中的分布、对溶酶体膜相关蛋白的抑制活性和溶酶体膜组成成分的影响，揭示溶酶体膜渗透（LMP）与溶酶体介导的细胞死亡之间的关系和细胞死亡机制，并结合体内试验验证所设计的化合物的抗肿瘤活性和逆转耐药活性，为发现抗肿瘤活性强、选择性高的有效药物奠定研究基础。

The lysosomes in cancer cells are more numerous, larger and with more fragile lysosome membrane than those in normal cells. The lysosome related cell death may prove useful strategy in cancer treatment, and provided that cancer cell lysosomes can be specifically targeted. Based on our previous results related to three type of natural products targeting lysosomes, we designed to synthesize derivatives with different PKa value by modify these structures with basic substitutes.Mechanism investigation will reveal the relationships between structure and lysosomal targeting, and the rules between lysosomal involved cell deaths with the lysomal membrane permeablization (LMP). Anticancer effect and the reversing activities towards MDR of synthesized drivatives both in vitro and in vivo are furtherly evaluated. Taken together, this project provides evidences for discovery of new drugs with potent and high selective properties.