氨甲酰基糖修饰的萘酰亚胺类化合物的合成及其靶向抗肿瘤作用研究

Based on the specific carbohydrate antigens of the cancer cells, discovering the recognition system of distinguishing normal cell and cancer cell, and developing specifically diagnostic agents, molecular-targeted anticancer drugs, vaccines and targeting drug-delivery system have important implications for exploring efficient and novel methods for cancer diagnosis, prevention and treatment. In this project, considering the highly selective affinity of carbamoylmannose to the breast cancer, a series of naphthalimide derivatives conjugated with carbamoylsugars and carbamoylazasugars are designed and synthesized for developing novel specifically molecular-targeted anticancer drugs and diagnostic agents. Their selective interactions between the cancer cells and the normal cells, the tumor targeting to the different cancer cells, the targeted anticancer activities, and furthermore, the mechanisms of the recognition to cancer cells and the interaction to DNA, as well as their structure-activity relationships will be investigated. With the above research, novel tumor targeting carbohydrate systems, molecular-targeted anticancer drugs and tumor targeting imaging agents would be developed. Moreover, this project will open new research directions for developing molecular-targeted anticancer drugs and imaging agents based on the specific carbohydrate recognitions, and for glycochemistry and glycobiology.

基于肿瘤细胞表面特异性糖类抗原，发现可分辨肿瘤细胞和正常细胞的特异性识别体系，开发新的特异性肿瘤诊断试剂、分子靶向抗肿瘤药物、疫苗和药物传输体系，对于探索癌症有效诊断、预防和治疗的新方法具有重要意义。本项目基于氨甲酰基甘露糖衍生物对乳腺癌细胞的高度选择性，设计合成系列氨甲酰基糖类和氮杂糖类衍生物，进一步与具有良好抗肿瘤活性和荧光成像性能的萘酰亚胺类化合物结合，合成系列靶向性糖类分子修饰的萘酰亚胺化合物，研究其对不同肿瘤细胞和正常细胞的靶向选择性和抗肿瘤活性以及荧光成像作用；发现新的靶向性糖类分子结构，研究糖类分子结构与细胞靶向性构效关系，探讨氨甲酰基糖类分子的引入对化合物选择性抗肿瘤活性和作用机制的影响；开发基于糖类小分子的靶向抗肿瘤药物和荧光成像试剂，为糖化学和糖生物学的研究开拓新的研究方向。

基于肿瘤细胞表面特异性糖类抗原，发现可分辨肿瘤细胞和正常细胞的特异性识别体系，开发新的特异性肿瘤诊断试剂、分子靶向抗肿瘤药物、疫苗和药物传输体系，对于探索癌症有效诊断、预防和治疗的新方法具有重要意义。本项目基于糖类分子与肿瘤细胞表面糖受体的选择性识别作用，分别设计合成了氨甲酰基甘露糖、甘露糖、乳糖和氮杂糖等修饰的喜树碱、萘酰亚胺类和苝酰亚胺类化合物，系统研究了超分子组装体的结构及光谱性质及其多效价糖基介导的抗肿瘤作用、光动力治疗作用、肿瘤靶向识别及细胞成像、肿瘤细胞内可调控的识别作用和多效价糖苷酶抑制活性等。发现了具有开发潜力的靶向性肿瘤光动力治疗体系和肿瘤细胞内的荧光成像和温敏效应组装体；建立了评价自组装多效价糖苷酶抑制剂小鼠体内降血糖活性的实验方法，为自组装多效价糖苷酶抑制剂在糖尿病治疗方面的应用奠定了基础。本项目研究成果为多效价糖基介导的生物效应研究做了有益探索和尝试，为糖化学和糖生物学研究开辟了新的方向。