超分子氮杂糖簇组装体的制备及其糖苷酶抑制活性研究

Glycosidase is one of the key enzymes in carbohydrate metabolism. The occurrence and development of some major diseases, such as diabetes, tumor, viral infection, immune disease, closely relate to the abnormal expression of glycosidase. Finding highly active glycosidase inhibitor is one of the important directions for developing antitumor, antidiabetes, antiviral and immune modulating drugs. Based on the very good inhibitory activity against glycosidase of azasugar and the multivalent effect in the sugar-protein interaction, in this project, series of new carbohydrate derivatives conjugated with phenylalanine peptides and fatty acids will be designed and synthesized, from which a series of novel supermolecular azasugar clusters with very good biological intermiscibility are fabricated with the aid of non-covalent intermolecular interactions, such as hydrogen bonding, π-π interaction, hydrophobic effects. The glycosidase inhibition and the interaction with the enzyme of the supermolecular glycoclusters will be investigated for developing novel highly active supermolecular glycosidase inhibitor and for understanding the recognition and interaction mechanism between the supermolecular glycocluster and the enzyme. This project will open a new research direction of developing glycosidase inhibitor from supermolecular glycoclusters based on the multivalent effect, and the results of this project would be of important theoretical significance for studying highly active supermolecular antidiabetes, antitumor, antiviral agents and for interpreting the recognition and interaction mechanism between sugar and protein.

糖苷酶是糖代谢关键酶之一，许多重大疾病如糖尿病、肿瘤、病毒性感染、免疫疾病等的发生、发展多伴随着细胞表面糖链的异常变化和糖苷酶的异常表达。因此，发现新的高活性糖苷酶抑制剂是目前抗肿瘤、抗糖尿病、抗病毒和免疫调节剂药物研究的热点之一。基于氮杂糖优良的糖苷酶抑制活性以及糖-蛋白相互作用的多价效应，本课题拟设计合成一类新的脂肪酸-苯丙氨酸肽-氮杂糖缀合物，利用分子间氢键、π-π作用以及脂肪链的疏水诱导作用等，构筑具有良好生物相容性的超分子氮杂糖簇组装体，发现高活性超分子糖苷酶抑制剂，研究超分子糖簇组装体的结构，模拟与糖苷酶的识别和作用机制。本课题开辟了糖苷酶抑制剂研究和功能化超分子研究相结合的新方向，对于进一步研究新型高效超分子抗肿瘤、抗糖尿病、抗病毒，阐释糖-蛋白质的识别及作用机理具有重要理论意义。

糖苷酶是糖代谢关键酶之一，许多重大疾病如糖尿病、肿瘤、病毒性感染、免疫疾病等的发生、发展多伴随着细胞表面糖链的异常变化和糖苷酶的异常表达。发现新的高活性糖苷酶抑制剂对开发新型抗肿瘤、抗糖尿病、抗病毒和免疫调节剂药物具有重要意义。本课题基于氮杂糖优良的糖苷酶抑制活性以及糖-蛋白相互作用的多价效应，设计合成了系列新的苝酰亚胺-野尻霉素缀合物、两亲性脂肪链-野尻霉素衍生物、苝酰亚胺-糖基缀合物和功能化苝酰亚胺-糖类衍生物，借助芳香环的π-π相互作用和脂肪链的疏水作用等，构筑了具有良好生物相容性的超分子糖簇组装体；组装体表现出显著的多效价糖苷酶抑制活性和对α-糖苷酶的选择性，并可有效降低小鼠体内的餐后血糖水平，呈现出显著的多效价作用。首次将超分子多效价糖苷酶抑制剂用于小鼠体内降糖活性研究。同时，探讨了超分子糖簇组装体与蛋白质（凝集素）的选择性结合作用、抗肿瘤活性、离子识别、细胞成像及温敏效应，以及稠杂氮杂糖类衍生物的合成及糖苷酶抑制活性等。本项目研究成果为进一步开展新型功能化糖簇组装体的构筑及其生物学功能研究，尤其是自组装多效价糖苷酶抑制剂在糖尿病治疗方面的应用研究奠定了基础。