新型天然α-葡萄糖苷酶抑制剂Penasulfate A 及其衍生物的合成、活性研究

Diabetes mellitus is one of the most life-threatening diseases worldwide. Traditional antidiabetic drugs have side effects, such as gastrointestinal discomfort, hypoglycaemia and decreased body weight. In contrast, α-glucosidase inhibitor can control postprandial plasma glucose level effectively. It delays but does not prevent the absorption of carbohydrates, has been recognized as an effective and potential antidiabetic drug. Thus, finding novel good α-glucosidase inhibitor is of great significance for the development of new antidiabetic drugs. This project is devoted to syntheses of novel α-glucosidase inhibitor Penasulfate A and its derivatives in a convergent manner using available carbohydrates and Roche esters as chiral pool through key olefin cross-metathesis (CM) and Heck coupling. In-vitro biological activities of all the target compounds will also be evaluated to disclose the relationship between the α-glucosidase inhibitory activity and structure. Besides, some compounds with excellent α-glucosidase inhibitor activity will be further carried out in-vivo bioassay. The merit of the project is to provide more valuable lead compounds for the development of alternative antidiabetic drugs and therapeutic strategies.

糖尿病是当今社会威胁人类健康的最主要疾病之一。传统的降血糖药物往往有胃肠道不适、低血糖和体重减轻等副作用，而α–葡萄糖苷酶抑制剂可有效降低餐后的血糖水平，且它只延缓而不阻止碳水化合物的吸收，被视为理想的有应用前景的治疗药物，因而寻找抑制活性优良的α–葡萄糖苷酶抑制剂对降血糖新药的研发至关重要。该项目以天然单糖和Roche酯为手性源，采用汇聚式合成策略，应用烯烃复分解反应（CM）和Heck反应为关键反应合成天然α-葡萄糖苷酶抑制剂Penasulfate A及其衍生物，并对这些化合物进行体外α-葡萄糖苷酶抑制活性测试，研究它们的构效关系，揭示Penasulfate A的关键活性部位，并筛选出的活性优良的先导化合物进行体内动物试验，为糖尿病治疗新药的开发奠定前期的实验基础。

Penasulfate A是从海洋生物海绵中分离出来的天然产物，是由哌啶甲酸甲酯与一含有甲基立体中心、两个硫酸酯的饱和脂肪酸组成的酰胺结构，其表现出较好的α-葡萄糖苷酶抑制活性（IC50 = 4.4 μM）。本项目主要研究内容是完成对新型α-葡萄糖苷酶抑制剂海洋天然产物Penasulfate A及其结构类似物的合成，并进行体外的α-葡萄糖苷酶抑制活性测试。该项目采用高度汇聚式的合成策略，以关键的烯烃复分解反应、Suzuki偶联、亚铜盐催化的偶联反应为主要反应最长线性14步共20步完成Penasulfate A及其C14、C15位的非对映异构体化合物27合成。该项目测试了Penasulfate A、前体二醇、亚异丙基保护的二醇化合物2对α–葡萄糖苷酶(C5003) 的抑制活性，其IC50值分别为0.011、0.171、1.108 mmol/L，Penasulfate A及其C14、C15位的非对映异构体对α–葡萄糖苷酶(G0660) 的IC50值分别为9.62、10.64 μmol/L，表明Penasulfate A及其衍生物均有较好的α–葡萄糖苷酶抑制活性。通过Penasulfate A及其C14、C15位的非对映异构体27的数据与天然产物的比对，合成的Penasulfate A可能并非天然产物，仅是报道结构的天然产物，天然产物的真实结构可能需要重新确认。该项目的合成路线为今后类似结构天然产物的合成提供了借鉴经验，生物活性测试表明Penasulfate A及其衍生物均有较好的α–葡萄糖苷酶抑制活性。