海绵来源PTP1B抑制剂类降血糖先导化合物的发现与作用机制研究

China is a large country with diabetes. In adults over 18 years of age, the estimated prevalence of diabetes according to the latest international clinical diagnostic criteria is as high as 11.6%. Protein tyrosine phosphatase 1B (PTP1B) is an important target in the treatment of type 2 diabetes mellitus. This project is intended to systematically study the hypoglycemic constituents of two marine sponge of Reniochalina stalagmitis and Haliclona simulans, based on the discovery of a series of compounds with significant PTP1B inhibitory activity. The selected marine sponges were applied the anti-diabetes activity screening model in vitro, combined with UHPLC-Q/Exactive-MS and DAD-HPLC-NMR chromatography/spectroscopy hyphenated techniques to isolate the active compounds from two marine sponges, respectively. The absolute structures of new compounds were determined by extensive spectroscopic analyses and calculated ECD spectra. The PTP1B inhibitory activity of the isolated compounds was evaluated to discuss their structure-activity relationship. The anti-diabetes biological mechanism of the potent biological metabolites will also be studied. The project intended to discover the new leads with significant potent anti-diabetes activity, which can provide an important basis for the rational and efficient use of marine sponge resources.

中国是糖尿病大国，18岁以上成人样本中，根据国际最新临床诊断标准进行诊断的糖尿病估测患病率高达11.6％。蛋白酪氨酸磷酸酶1B（PTP1B）是治疗Ⅱ型糖尿病的重要靶标。本项目拟在发现一系列具有显著PTP1B抑制活性的化合物的基础上，系统研究两种海绵Reniochalina stalagmitis和Haliclona simulans的降血糖活性成分。利用体外抗糖尿病活性筛选模型指导追踪分离，结合UHPLC-Q/Exactive-MS与DAD-HPLC-NMR等色谱/波谱联用技术，定向追踪分离该两种海绵中的活性化合物。运用现代波谱学技术结合计算化学的方法，确定单体化合物的平面及绝对构型。评价化合物的PTP1B抑制活性，探讨其构效关系，研究强活性化合物的降糖作用机制。旨在发现活性显著、作用机制明确的新型抗糖尿病先导化合物，为我国海绵药用资源的发掘利用提供重要依据。

蛋白酪氨酸磷酸酶1B（PTP1B）是治疗Ⅱ型糖尿病的重要靶标。本项目拟在发现一系列具有显著PTP1B抑制活性的化合物的基础上，系统研究两种西沙海绵肾指海绵Reniochalina stalagmitis和相似蜂海绵Haliclona simulans的降血糖活性成分。利用体外抗糖尿病活性筛选模型指导追踪分离，结合LC/MS与DAD-HPLC-NMR等色谱/波谱联用技术，定向追踪分离该两种海绵中的活性化合物。运用现代波谱学技术结合计算化学的方法，确定单体化合物的平面及绝对构型。共分离23个化合物，其中新化合物4个，其中12个科内首分，3个属内首分。为探索具有抗肿瘤活性和抑制蛋白酪氨酸磷酸酶1B（PTP1B）活性的先导化合物，对分离到的部分化合物进行了初步的癌细胞生长抑制活性和PTP1B抑制活性的检测。对部分环肽化合物进行化学合成实验，初步合成出reniochalistatins C、reniochalistatins F、reniochalistatins G（A1）、reniochalistatins H（A2）、reniochalistatins J（A4）5个环肽化合物，分别为10 mg，15 mg，41 mg，90 mg和28 mg。为进一步探讨其构效关系，研究强活性化合物的降糖作用机制奠定前期基础。研究为发现活性显著、作用机制明确的新型抗糖尿病先导化合物，为我国海绵药用资源的发掘利用提供重要依据。