基于PTP1B蛋白酶的新型齐墩果酸N-苷糖化合物的设计、合成及抗II型糖尿病分子机制研究

开发更高效低毒且生物利用度高的抗II型糖尿病药物一直是医药领域的核心问题之一。而针对PTP1B蛋白靶点进行抗II型糖尿病药物筛选时，一直受限于PTP1B抑制剂的选择性和透膜性。前期研究中设计合成的齐墩果酸O-苷糖化合物可以显著抑制PTP1B的活性，同时对其同源酶有一定的选择性。进一步设计合成的N-苷糖化合物，对PTP1B显示出更强的抑制活性，且对TCPTP具有更高的选择性。基于此，本项目利用分子模拟和化学合成技术，明确PTP1B抑制剂-齐墩果酸N-苷糖化合物的新型结构和制备方法；通过酶活测试、体内外细胞和动物模型等分子生物学手段研究目标化合物的抗II型糖尿病的活性，阐明其构效关系和分子作用机制；利用平行人工膜渗透、Caco-2细胞和大鼠动物模型探索优选目标化合物的透膜性和体内药代动力学过程。本项目可望获得安全高效、透膜性良好的PTP1B抑制剂，为开发抗II型糖尿病药物提供基础支撑。

The development of anti-type II diabetes drugs with more efficient, low toxicity and high bioavailability has been one of the core issues in the field of medicine. However, the endeavor to search for therapeutic PTP1B inhibitors proved largely abortive. The major reason could be the nature of the PTP1B catalytic site with highly conservative and cationic characteristic, which makes most PTP1B inhibitors with inadequate cell permeability and low selectivity for PTP1B over the most homogeneous T-cell protein tyrosine phosphatase (TCPTP). In our previous work, we modified the structure of oleanolic acid with sugar moiety at the C-3 position and the long acidic chain at C-28 position through an ester linkage affording a series of oleanolic acid O-glyocisdes, of which the PTP1B inhibitory activities in vitro were evaluated and the preliminary structure-activity relationships (SARs) were confirmed. In order to search for the new lead compound with stronger PTP1B inhibitory activities and weaker toxicity, oleanolic acid N-glycosides were designed and synthesized, and exihibited good PTP1B inhibitory activities and remarkably potent selectivity over highly homologous TCPTP. Based on the above results, this project established the pharmacophore model by computer aided drug design technology, and will continue to design and synthesize the new sugar-based oleanolic acid N-glycosides derivatives, and then their anti-type II diabetic activities will be evaluated by molecular bio-techniques (Enzyme activity test, in vitro and in vivo cell and animal model). Based on these studies, we could confirm the structure-activity relationships (SARs) and the molecular mechanism. And then we will explore the permeability and in vivo pharmacokinetics of the target compound by parallel artificial membrane permeation, Caco-2 cells and rat model. This project is expected to obtain a safe and efficient PTP1B inhibitor with good permeability, which will provide basic support for the development of anti-type II diabetes.