Design, synthesis and biological evaluation of vincamine derivatives as potential pancreatic beta-cells protective agents for the treatment of type 2 diabetes mellitus
Design, synthesis and biological evaluation of vincamine derivatives as potential pancreatic beta-cells protective agents for the treatment of type 2 diabetes mellitus
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长春胺衍生物作为治疗 2 型糖尿病的潜在胰腺 β 细胞保护剂的设计、合成和生物学评价
DOI：
10.1016/j.ejmech.2019.111976
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发表时间：
2020
影响因子：
6.7
通讯作者：
Hu Lihong
中科院分区：
文献类型：
--
作者：
Wang Junwei;Lv Xue;Xu Jiawen;Liu Xinpeng;Du Te;Sun Guanglong;Chen Jing;Shen Xu;Wang Jiaying;Hu Lihong
设计、合成并评价了一系列长春花碱类化合物作为2型糖尿病胰腺β细胞的保护剂。大多数化合物显示出强大的胰腺β细胞保护活性，五种衍生物的活性比长春花碱高20-50倍。尤其是化合物Vin-C01和Vin-F03，其EC50值分别为0.22%μM和0.27%μM。它们的胰腺β细胞保护活性大约是长春花碱的2倍。在细胞存活率实验中，Vin-C01和Vin-F03能有效促进β-细胞存活，保护β-细胞免受链脲佐菌素诱导的细胞凋亡。进一步的细胞作用机制研究表明，其强大的β细胞保护活性是通过调节IRS2/PI3K/Akt信号通路实现的。本研究表明，与长春花碱相比，化合物Vin-C01和Vin-F03是两种更有效的胰腺β细胞保护剂，有望成为治疗2型糖尿病的主要候选药物。
A series of vincamine derivatives were designed, synthesized and evaluated as pancreatic β-cells protective agents for type 2 diabetes mellitus. Most of the compounds displayed potent pancreatic β-cells protective activities and five derivatives were found to exhibit 20–50-fold higher activities than vincamine. Especially for compoundsVin-C01andVin-F03, exhibited a remarkable EC50value of 0.22 μM and 0.27 μM, respectively. Their pancreatic β-cells protective activities increased approximately 2 times than vincamine. In cell viability assay, compoundsVin-C01andVin-F03could effectively promote β-cell survival and protect β-cells from STZ-induced apoptosis. Further cellular mechanism of action studies demonstrated that their potent β-cells protective activities were achieved by regulating IRS2/PI3K/Akt signaling pathway. The present study evidently showed that compoundsVin-C01andVin-F03were two more potent pancreatic β-cells protective agents compared to vincamine and might serve as promising lead candidates for the treatment of type 2 diabetes mellitus.