含尿嘧啶结构单元二肽衍生物的设计、合成及生物活性研究

Design, Synthesis and Biological Activity of Dipeptide Derivatives Bearing Uracil Unit

为探索新型抗糖尿病分子,设计了含有尿嘧啶结构单元的二肽衍生物.以尿嘧啶、多聚甲醛和半胱氨酸为原料,经过两步反应获得关键中间体S-胸腺嘧啶-L-半胱氨酸(IM-2),再经氨基保护、羧基酯化和氨基酸偶联,顺利合成了16个二肽衍生物.所得目标化合物均经1H NMR、13C NMR和HRMS进行结构确认,并开展了过氧化物酶体增殖物受体反应元件(PPRE)激动活性、α-葡萄糖苷酶-rat抑制活性、二肽基肽酶-4(DPP-4)抑制活性筛选.生物活性结果显示,这些二肽衍生物的PPRE相对激动活性、α-葡萄糖苷酶和DPP-4抑制活性都很弱;同时发现,该类分子的α-葡萄糖苷酶抑制活性变化趋势与PPRE激动活性、DPP-4抑制活性变化趋势相反,这为新型多肽多靶点药物的设计提供了新思路.

In order to explore a new type of anti-diabetic molecules, dipeptide derivatives containing uracil structural units were designed. The key intermediate S-thymine-L-cysteine (IM-2) was obtained from uracil, paraformaldehyde and cysteine through two step reactions, and then 16 dipeptide derivatives were successfully synthesized through amino protection, carboxylation and amino acid coupling. All new compounds have been characterized by 1H NMR, 13C NMR and HRMS, and the peroxisome proliferator response element (PPRE) activated activity,α-glucosidase-rat inhibitory activity and dipeptidyl peptidase-4 (DPP-4) inhibitory activity were screened for all target molecules. The results showed that these molecules had weak above-mentioned activities, meanwhile the change trend of α-glucosidase-rat inhibitory activity of these molecules is opposite to that of PPRE agonistic activity and DPP-4 inhibitory activity. It maybe provides an idea for the research of designing novel polypeptide multi-target drugs.